Non-fused thiophene derivatives and their uses

ABSTRACT

The present invention relates to a new class of non-fused thiophene derivatives and their uses for treating diseases such as infection, cancer, metabolic diseases, cardiovascular diseases, iron storage disorders and inflammatory disorders.

CROSS-REFERENCE TO RELATED APPLICATION

This application is the U.S. national stage application of InternationalPatent Application No. PCT/EP2019/053077, filed Feb. 8, 2019.

The Sequence Listing for this application is labeled “Seq-List.txt”which was created on Jul. 5, 2020 and is 1 KB. The entire content of thesequence listing is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to the field of medicine, in particularnon-fused thiophene derivatives and their uses for treating diseasessuch as infection, cancer, metabolic diseases, cardiovascular diseases,iron storage disorders and inflammatory disorders.

BACKGROUND OF THE INVENTION

Viruses are small infectious agents that replicates only inside livingcells of other organisms. They can infect all types of life forms, fromanimals and plants to microorganisms, including bacteria and archaea.Among them, more than 400 species of virus are known to be responsibleof diseases in humans, many of them leading to serious pathologies andeventually death. In particular, HIV was classified at the sixth leadingcause of death worldwide in 2012 with 1.5 million deaths per year (WHO,Fact sheet No 310, 2014). Seasonal influenza viruses are responsible offlu that affects approximately 20% of the world population and causes250,000 to 500,000 deaths per year (WHO, Fact sheet No 211, 2014). Amongother examples, Hepatitis B and C are responsible altogether for about1.4 million of death each year and human Papillomaviruses areresponsible of cervix cancer, the second most common women cancerworldwide, leading to 270,000 death in 2012 (WHO, Fact sheets, 2016).

Because viruses use vital metabolic pathways within host cells toreplicate, they are difficult to eliminate without using drugs thatcause toxic effects to host cells in general. The most effective medicalapproaches to viral diseases are vaccinations to provide immunity toinfection, and antiviral drugs that selectively interfere with viralreplication. Vaccines are very effective on stable viruses for apreventive use. However, vaccines are of limited use in treating apatient who has already been infected. They are also difficult tosuccessfully deploy against rapidly mutating viruses, such as influenza(the vaccine for which is updated every year) and HIV. Antiviral drugsmay be particularly useful in these cases.

Antiviral drugs are a class of medication used specifically for treatingviral infections. Antiviral drugs do not destroy their target pathogens,instead they inhibit their development. Antiviral drugs may target anystage of the viral life cycle: attachment to a host cell, release ofviral genes and possibly enzymes into the host cell, replication ofviral components using host-cell machinery, assembly of viral componentsinto complete viral particles, and release of viral particles to infectnew host cells. The most common antiviral drugs are nucleoside analoguesthat block viruses' replication. Most antiviral drugs are used forspecific viral infections, while broad-spectrum antiviral drugs areeffective against a wide range of viruses.

Soon after the development of antiviral drugs, resistance appeared.Antiviral drug resistance can be defined as a decreased susceptibilityto a drug through either a minimally effective, or completelyineffective, treatment response to prevent associated illnesses from aparticular virus. Antiviral drug resistance remains a major obstacle toantiviral therapy as it has developed to almost all specific andeffective antiviral drugs. For example, there are two main groups ofantiviral drugs available for treatment and prophylaxis of influenza: M2inhibitors (amantadine and rimantadine) and neuraminidase inhibitors(oseltamivir and zanamivir). Despite the effectiveness of these drugs inreducing influenza-related morbidity and mortality, the emergence ofdrug resistance poses a critical limitation on their application andhave raised an urgent need for developing new anti-influenza drugsagainst resistant forms.

Thus, there is nowadays a strong need for the development of newantiviral drugs, and in particular broad-spectrum antiviral drugs. Thepresent invention seeks to meet these and other needs.

SUMMARY OF THE INVENTION

The present invention provides a new compound of formula (I):

-   -   wherein:        -   R₁ represents:            -   a hydrogen;            -   a 3-10 membered ring, saturated or unsaturated selected                in the group consisting of an aryl, a cycloalkyl, a                heterocycloalkyl, a fused arylheterocycloalkyl, a fused                heteroarylcycloalkyl, a fused bicycloalkyl, and a                bridged carbocyclyl, said 3-10 membered ring is                optionally substituted by at least one radical selected                in the group consisting of:                -   a halogen,                -   a (C₁-C₆)alkyl or a (C₁-C₆)alkyloxy optionally                    substituted by at least one halogen, preferably                    optionally substituted by at least one fluorine, and                -   a hydroxy,                -   a —CO—R₆ or a —CO₂R₆ with R₆ being a hydrogen or a                    (C₁-C₆)alkyl, and                -   an optionally substituted aryl, or            -   a (C₁-C₆)alkyl, optionally substituted by at least one                radical selected in the group consisting of:                -   a halogen, preferably a fluorine,                -   a (C₁-C₆)alkyloxy optionally substituted by at least                    one halogen, preferably optionally substituted by at                    least one fluorine, and                -   a 3-10 membered ring as defined above;        -   R₂ represents:            -   a hydrogen,                -   a halogen,                -   a (C₁-C₆)alkyl optionally substituted by at least                    one halogen, preferably optionally substituted by at                    least one fluorine,                -   an optionally substituted aryl, or                -   an optionally substituted cycloalkyl;        -   R₃ represents:            -   a 5-10 membered ring, saturated or unsaturated selected                in the group consisting of:                -   an aryl optionally fused to a heterocycloalkyl,                    preferably selected from the group consisting of a                    dioxole, a morpholine, a dioxane, a tetrahydropyran,                    and a tetrahydrofuran,                -   a heteroaryl,                -   a cycloalkyl,                -   a heterocycloalkyl, and                -   a 5-10 membered bridged carbocyclyl or heterocyclyl,                    said 5-10 membered ring is optionally substituted by                    at least one radical selected in the group                    consisting of:                -    a halogen,                -    a (C₁-C₆)alkyl optionally substituted by at least                    one halogen, preferably optionally substituted by at                    least one fluorine, or by an optionally bridged                    heterocycloalkyl optionally substituted by a                    (C₁-C₆)alkyl,                -    a —NH—(C₁-C₆)alkyl or a —N—((C₁-C₆)alkyl)₂,                    optionally substituted by at least one radical                    selected in the group consisting of a                    heterocycloalkyl, a cycloalkyl, a hydroxyl, a                    thiacycloalkyl-1,1dioxide and a (C₁-C₆)alkyloxy,                -    a —NH-heterocycloalkyl, a —NH-cycloalkyl, a                    —N((C₁-C₆)alkyl)-heterocycloalkyl, or a                    —NH((C₁-C₆)alkyl)-thiacycloalkyl-1,1dioxide,                    optionally substituted by a hydroxyl, a                    (C₁-C₆)alkyl, a (C₁-C₆)alkyloxy or a —CO—R₆ with R₆                    being a hydrogen or a (C₁-C₆)alkyl,                -    a hydroxy, a —CN, a —CO—R₆ or a —CO₂R₆ with R₆                    being a hydrogen or a (C₁-C₆)alkyl,                -    a (C₁-C₆)alkyloxy optionally substituted by at                    least one radical selected in the group consisting                    of a halogen, preferably a fluorine, a hydroxy, a                    (C₁-C₆)alkyloxy, a —NR₇R₈ with R₇ and R₈ are                    independently a hydrogen or a (C₁-C₆)alkyl, a                    —NHCOR₉, a —NHCO₂R₉, with R₉ being a (C₁-C₆)alkyl, a                    —CO₂R₆ with R₆ being a hydrogen or a (C₁-C₆)alkyl,                    and a heterocycle,                -    a —NHCOR₉, a —NHCO₂R₉, or a —SO₂R₉, with R₉ being a                    (C₁-C₆)alkyl, and                -    a heterocycloalkyl, a bridged heterocycloalkyl, a                    heterocycloalkyloxy, a cycloalkyloxy, a                    thiaheterocycloalkyl-1,1-dioxide or a                    spiroheterocycloalkyl, optionally substituted by a                    (C₁-C₆)alkyl, a (C₁-C₆)alkyloxy, a hydroxy, a                    ketone, a halogen or a (C₁-C₆)alkyl optionally                    substituted by a (C₁-C₆)alkyloxy, or            -   a (C₁-C₆)alkyl or a (C₂-C₆)alkenyl, optionally                substituted by a 5-10 membered ring as defined above or                a —CO₂R₆ with R₆ being a hydrogen or a (C₁-C₆)alkyl;        -   R₄ represents —COOH; and        -   R₅ represents:            -   a hydrogen, or            -   a (C₁-C₆)alkyl;    -   with the proviso that when R₁ is a phenyl or a phenyl        substituted by a bromine, a methyl, a methoxy or an ethoxy, then        R₃ is not a phenyl substituted by a tert-butyl; and    -   with the proviso that when R₁ is a hydrogen, then R₃ is a 5-10        membered ring and R₂ is an optionally substituted aryl or an        optionally substituted cycloalkyl;    -   and the stereoisomers, and the pharmaceutical salts thereof.

The present invention further relates to a compound for use for treatinga disease selected from the group consisting of an infection, preferablya viral or a bacterial infection, a cancer, a metabolic disease, acardiovascular disease, an inflammatory disorder, and iron storagedisease/disorder wherein the compound has the formula (I):

-   -   wherein:        -   R₁ represents:            -   a 3-10 membered ring, saturated or unsaturated selected                in the group consisting of an aryl, a cycloalkyl, a                heterocycloalkyl, a fused arylheterocycloalkyl, a fused                heteroarylcycloalkyl, a fused bicycloalkyl, and a                bridged carbocyclyl, said 3-10 membered ring is                optionally substituted by at least one radical selected                in the group consisting of:                -   a halogen,                -   a (C₁-C₆)alkyl or a (C₁-C₆)alkyloxy optionally                    substituted by at least one halogen, preferably                    optionally substituted by at least one fluorine, and                -   a hydroxy,                -   a —CO—R₆ or a —CO₂R₆ with R₆ being a hydrogen or a                    (C₁-C₆)alkyl, and                -   an optionally substituted aryl, or            -   a (C₁-C₆)alkyl, optionally substituted by at least one                radical selected in the group consisting of:                -   a halogen, preferably a fluorine,                -   a (C₁-C₆)alkyloxy optionally substituted by at least                    one halogen, preferably optionally substituted by at                    least one fluorine, and                -   a 3-10 membered ring as defined above, or            -   a hydrogen;        -   R₂ represents:            -   a hydrogen,            -   a halogen,            -   a (C₁-C₆)alkyl optionally substituted by at least one                halogen, preferably optionally substituted by at least                one fluorine,            -   an optionally substituted aryl, or            -   an optionally substituted cycloalkyl;        -   R₃ represents:            -   a 5-10 membered ring, saturated or unsaturated selected                in the group consisting of:                -   an aryl optionally fused to a heterocycloalkyl,                    preferably selected from the group consisting of a                    dioxole, a morpholine, a dioxane, a tetrahydropyran,                    and a tetrahydrofuran,                -   a heteroaryl,                -   a cycloalkyl,                -   a heterocycloalkyl, and                -   a 5-10 membered bridged carbocyclyl or heterocyclyl,                -   said 5-10 membered ring is optionally substituted by                    at least one radical selected in the group                    consisting of:                -    a halogen,                -    a (C₁-C₆)alkyl optionally substituted by at least                    one halogen, preferably optionally substituted by at                    least one fluorine, or by an optionally bridged                    heterocycloalkyl optionally substituted by a                    (C₁-C₆)alkyl,                -    a —NH—(C₁-C₆)alkyl or a —N—((C₁-C₆)alkyl)₂,                    optionally substituted by at least one radical                    selected in the group consisting of a                    heterocycloalkyl, a cycloalkyl, a hydroxyl, a                    thiacycloalkyl-1,1dioxide and a (C₁-C₆)alkyloxy,                -    a —NH-heterocycloalkyl, a —NH-cycloalkyl, a                    —N((C₁-C₆)alkyl)-heterocycloalkyl, or a                    —NH((C₁-C₆)alkyl)-thiacycloalkyl-1,1dioxide,                    optionally substituted by a hydroxyl, a                    (C₁-C₆)alkyl, a (C₁-C₆)alkyloxy or a —CO—R₆ with R₆                    being a hydrogen or a (C₁-C₆)alkyl,                -    a hydroxy, a —CN, a —CO—R₆ or a —CO₂R₆ with R₆                    being a hydrogen or a (C₁-C₆)alkyl,                -    a (C₁-C₆)alkyloxy optionally substituted by at                    least one radical selected in the group consisting                    of a halogen, preferably a fluorine, a hydroxy, a                    (C₁-C₆)alkyloxy, a —NR₇R₈ with R₇ and R₈ are                    independently a hydrogen or a (C₁-C₆)alkyl, a                    —NHCOR₉, a —NHCO₂R₉, with R₉ being a (C₁-C₆)alkyl, a                    —CO₂R₆ with R₆ being a hydrogen or a (C₁-C₆)alkyl,                    and a heterocycle,                -    a —NHCOR₉, a —NHCO₂R₉, or a —SO₂R₉, with R₉ being a                    (C₁-C₆)alkyl, and                -    a heterocycloalkyl, a bridged heterocycloalkyl, a                    heterocycloalkyloxy, a cycloalkyloxy, a                    thiaheterocycloalkyl-1,1-dioxide or a                    spiroheterocycloalkyl, optionally substituted by a                    (C₁-C₆)alkyloxy, a hydroxy, a ketone, a halogen or a                    (C₁-C₆)alkyl optionally substituted by a                    (C₁-C₆)alkyloxy; or            -   a (C₁-C₆)alkyl or a (C₂-C₆)alkenyl, optionally                substituted by a 5-10 membered ring as defined above or                a —CO₂R₆ with R₆ being a hydrogen or a (C₁-C₆)alkyl;        -   R₄ represents —COOH; and        -   R₅ represents:            -   a hydrogen, or            -   a (C₁-C₆)alkyl optionally substituted by at least one                halogen, preferably optionally substituted by at least                one fluorine,                and the stereoisomers, and the pharmaceutical salts                thereof.

In a particular embodiment of formula (I), R₁ represents:

-   -   a fused arylheterocycloalkyl, a fused heteroarylcycloalkyl, a        fused bicycloalkyl, a cycloalkyl or an aryl, optionally        substituted by at least one radical selected in the group        consisting of:        -   a halogen,        -   a (C₁-C₆)alkyl optionally substituted by at least one            halogen, preferably optionally substituted by at least one            fluorine,        -   a (C₁-C₆)alkyloxy optionally substituted by at least one            halogen, preferably optionally substituted by at least one            fluorine, and        -   an optionally substituted phenyl,    -   a bridged carbocyclyl, or    -   a (C₁-C₆)alkyl optionally substituted by at least one halogen,        preferably optionally substituted by at least one fluorine.

In a particular embodiment of formula (I), R₁ represents:

-   -   a phenyl fused to a tetrahydropyran, a fused bicycloalkyl,    -   a cycloalkyl, optionally substituted by at least one radical        selected in the group consisting of:        -   a halogen, preferably a fluorine,        -   a (C₁-C₆)alkyl optionally substituted by at least one            halogen, preferably optionally substituted by at least one            fluorine, and        -   an optionally substituted phenyl,    -   an aryl, preferably a phenyl, optionally substituted by at least        one radical selected in the group consisting of:        -   a halogen, preferably a chlorine or a fluorine,        -   a (C₁-C₆)alkyl optionally substituted by at least one            halogen, preferably optionally substituted by at least one            fluorine, and        -   a (C₁-C₆)alkyloxy optionally substituted by at least one            halogen, preferably optionally substituted by at least one            fluorine, preferably a methoxy,    -   a bridged carbocyclyl, preferably a bridged cyclohexyl, or    -   a (C₁-C₆)alkyl optionally substituted by at least one halogen,        preferably optionally substituted by at least one fluorine.

In a further particular embodiment of formula (I), R₃ represents:

-   -   an aryl, preferably a phenyl, optionally substituted by at least        one radical selected in the group consisting of:        -   a heterocycloalkyl, optionally substituted by a            (C₁-C₆)alkyloxy,        -   a (C₁-C₆)alkyloxy or a (C₁-C₆)alkyl optionally substituted            by at least one halogen, preferably optionally substituted            by at least one fluorine, or a (C₁-C₆)alkyloxy,        -   a halogen,        -   a —NH—(C₁-C₆)alkyl or a —N—((C₁-C₆)alkyl)₂, optionally            substituted by a heterocycloalkyl or a (C₁-C₆)alkyloxy, and        -   a —NH-heterocycloalkyl.

In a preferred embodiment, R₃ represents:

-   -   a phenyl, optionally substituted by at least one radical        selected in the group consisting of:        -   a morpholinyl,        -   a —NH-tetrahydropyranyl,        -   a —NH—(C₁-C₆)alkyl, optionally substituted by a            tetrahydropyranyl or a (C₁-C₆)alkyloxy,        -   a —N—((C₁-C₆)alkyl)₂, optionally substituted by a            tetrahydropyranyl or a (C₁-C₆)alkyloxy,        -   an azetidinyl optionally substituted by a (C₁-C₆)alkyloxy,        -   a (C₁-C₆)alkyloxy, optionally substituted by at least one            halogen, preferably optionally substituted by at least one            fluorine, or a (C₁-C₆)alkyloxy,        -   a halogen, preferably a fluorine, and        -   a (C₁-C₆)alkyl optionally substituted by at least one            halogen, preferably optionally substituted by at least one            fluorine.

In a further particular embodiment of formula (I),

-   -   R₂ represents:        -   a hydrogen,        -   a halogen, preferably a chlorine, or        -   a (C₁-C₃)alkyl, preferably a methyl,            -   and    -   R₁ represents:        -   a phenyl fused to a tetrahydropyran, or a fused            bicycloalkyl,        -   a cycloalkyl, optionally substituted by at least one radical            selected in the group consisting of:            -   a halogen, preferably a fluorine,            -   a (C₁-C₆)alkyl optionally substituted by at least one                halogen, preferably optionally substituted by at least                one fluorine, and            -   an optionally substituted phenyl,        -   an aryl, preferably a phenyl, optionally substituted by at            least one radical selected in the group consisting of:            -   a halogen, preferably a chlorine or a fluorine,            -   a (C₁-C₆)alkyl optionally substituted by at least one                halogen, preferably optionally substituted by at least                one fluorine, and            -   a (C₁-C₆)alkyloxy, optionally substituted by at least                one halogen, preferably optionally substituted by at                least one fluorine, preferably a methoxy, or        -   a bridged carbocyclyl, preferably a bridged cyclohexyl.

In a further particular embodiment of formula (I),

-   -   R₂ represents:        -   a hydrogen,        -   a halogen, preferably a chlorine,        -   a (C₁-C₆)alkyl, preferably a methyl and an isopropyl,        -   an optionally substituted (C₃-C₆)cycloalkyl, preferably a            cyclohexyl, and        -   an optionally substituted aryl, preferably a phenyl, and    -   R₁ represents a hydrogen or a (C₁-C₆)alkyl optionally        substituted by at least one halogen, preferably optionally        substituted by at least one fluorine.

In a preferred embodiment, the new compound of formula (I) is selectedin the group consisting of:

-   2-Benzamido-4-(4-chlorophenyl)thiophene-3-carboxylic acid (Compound    #1);-   2-Benzamido-4-(4-chloro-3-fluoro-phenyl)thiophene-3-carboxylic acid    (Compound #2);-   2-Benzamido-4-(4-chlorophenyl)-5-methyl-thiophene-3-carboxylic acid    (Compound #4);-   4-(4-Chlorophenyl)-2-[[4-(difluoromethoxy)benzoyl]amino]-5-methyl-thiophene-3-carboxylic    acid (Compound #5);-   2-Benzamido-5-chloro-4-(4-chloro-3-fluoro-phenyl)thiophene-3-carboxylic    acid (compound #6);-   2-Benzamido-4-norbornan-2-yl-thiophene-3-carboxylic acid (Compound    #9);-   2-Benzamido-4-cyclopentyl-thiophene-3-carboxylic acid (Compound    #10);-   4-Cyclohexyl-2-[[4-(difluoromethoxy)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #11);-   2-Benzamido-5-chloro-4-cyclohexyl-thiophene-3-carboxylic acid    (Compound #12);-   5-Chloro-4-cyclohexyl-2-[[4-(difluoromethoxy)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #13);-   5-Chloro-4-cyclohexyl-2-[(2-methylbenzoyl)amino]thiophene-3-carboxylic    acid (Compound #14);-   5-Chloro-4-cyclohexyl-2-[(4-morpholinobenzoyl)amino]thiophene-3-carboxylicacid    (Compound #15);-   2-Benzamido-5-chloro-4-cyclopentyl-thiophene-3-carboxylic acid    (Compound #18);-   2-Benzamido-4-[4-(trifluoromethyl)phenyl]thiophene-3-carboxylic acid    (Compound #20);-   2-Benzamido-4-(p-tolyl)thiophene-3-carboxylic acid (Compound #21);-   2-Benzamido-4-(3,4-dimethylphenyl)thiophene-3-carboxylic acid    (Compound #22);-   2-Benzamido-5-chloro-4-(3,4-dimethylphenyl)thiophene-3-carboxylic    acid (Compound #23);-   2-Benzamido-5-chloro-4-(p-tolyl)thiophene-3-carboxylic acid    (Compound #24);-   4-Cyclohexyl-2-[(3,4-dimethoxybenzoyl)amino]thiophene-3-carboxylic    acid (Compound #25);-   2-Benzamido-4-cyclohexyl-thiophene-3-carboxylic acid (Compound #26);-   2-Benzamido-4-cyclohexyl-5-methyl-thiophene-3-carboxylic acid    (Compound #27);-   2-[[4-(Difluoromethoxy)benzoyl]amino]-4-phenyl-thiophene-3-carboxylic    acid (Compound #28);-   4-Cyclohexyl-2-[(4-morpholinobenzoyl)amino]thiophene-3-carboxylic    acid (Compound #29);-   2-[[4-(Difluoromethoxy)benzoyl]amino]-5-methyl-4-phenyl-thiophene-3-carboxylic    acid (Compound #30);-   5-Chloro-2-[[4-(difluoromethoxy)benzoyl]amino]-4-phenyl-thiophene-3-carboxylic    acid (Compound #31);-   2-Benzamido-4-tert-butyl-thiophene-3-carboxylic acid (Compound #32);-   2-Benzamido-5-chloro-4-phenyl-thiophene-3-carboxylic acid (Compound    #33);-   2-Benzamido-5-methyl-4-phenyl-thiophene-3-carboxylic acid (Compound    #34);-   2-Benzamido-4-(3,3-difluorocyclobutyl)thiophene-3-carboxylic acid    (Compound #35);-   2-Benzamido-4-(3-chlorophenyl)thiophene-3-carboxylic acid (Compound    #36);-   2-Benzamido-4-norcaran-7-yl-thiophene-3-carboxylic acid (Compound    #37);-   2-Benzamido-4-(4-methoxyphenyl)thiophene-3-carboxylic acid (Compound    #38);-   2-Benzamido-4-(2,2,3,3-tetramethylcyclopropyl)thiophene-3-carboxylic    acid (Compound #39);-   2-Benzamido-4-methyl-5-phenyl-thiophene-3-carboxylic acid (Compound    #40);-   5-Cyclohexyl-2-[[4-(difluoromethoxy)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #41);-   2-[(2-Methylbenzoyl)amino]-4-phenyl-thiophene-3-carboxylic acid    (Compound #42);-   2-Benzamido-4-phenyl-thiophene-3-carboxylic acid (Compound #43);-   2-Benzamido-4-(2-chlorophenyl)thiophene-3-carboxylic acid (Compound    #44);-   2-[(2-Methylbenzoyl)amino]-5-phenyl-thiophene-3-carboxylic acid    (Compound #45);-   2-[(3,4-Dimethoxybenzoyl)amino]-4-phenyl-thiophene-3-carboxylic acid    (Compound #46);-   2-Benzamido-4-(trans-4-tert-butylcyclohexyl)thiophene-3-carboxylic    acid (Compound #48);-   2-Benzamido-5-chloro-4-[4-(trifluoromethyl)phenyl]thiophene-3-carboxylic    acid (Compound #50);-   2-Benzamido-4-(cis-4-tert-butylcyclohexyl)thiophene-3-carboxylic    acid (Compound #54);-   4-Cyclopentyl-2-[(4-morpholinobenzoyl)amino]thiophene-3-carboxylic    acid (Compound #59);-   4-Cyclopentyl-2-[[4-(tetrahydropyran-4-ylamino)benzoyl]    amino]thiophene-3-carboxylic acid (Compound #60);-   4-Cyclopentyl-2-[[4-(2-methoxyethylamino)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #61);-   4-Cyclopentyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #62);-   2-Benzamido-4-(3-phenylcyclobutyl)thiophene-3-carboxylic acid    (Compound #63);-   4-Cyclopentyl-2-[[4-(tetrahydropyran-4-ylmethylamino)    benzoyl]amino]thiophene-3-carboxylic acid (Compound #66);-   4-Cyclopentyl-2-[(3-morpholinobenzoyl)amino]thiophene-3-carboxylic    acid (Compound #71);-   2-Benzamido-4-chroman-3-yl-thiophene-3-carboxylic acid (Compound    #84);-   2-Benzamido-4-chroman-2-yl-thiophene-3-carboxylic acid (Compound    #85);-   2-Benzamido-4-cyclopropyl-thiophene-3-carboxylic acid (Compound    #87);-   4-Cyclopropyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #88);-   4-Cyclopropyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]    amino]thiophene-3-carboxylic acid (Compound #90);-   4-Tert-butyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]    thiophene-3-carboxylic acid (Compound #91);-   4-tert-Butyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #92);-   4-Chroman-3-yl-2-[[4-(2-methoxyethoxy)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #95);-   2-Benzamido-4-isobutyl-thiophene-3-carboxylic acid (Compound #96);-   4-Cyclobutyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #97);-   2-Benzamido-4-cyclobutyl-thiophene-3-carboxylic acid (Compound #98);-   4-Cyclobutyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]    amino]thiophene-3-carboxylic acid (Compound #99);-   2-[[4-(3-Methoxyazetidin-1-yl)benzoyl]amino]-4,5-dimethyl-thiophene-3-carboxylic    acid (Compound #100);-   4,5-Dimethyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]    thiophene-3-carboxylic acid (Compound #102);-   4-tert-Butyl-2-[[4-(2-methoxyethylamino)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #103);-   4-tert-Butyl-2-[[4-(3-ethoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #104);-   4-tert-Butyl-2-[[4-(tetrahydropyran-4-ylamino)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #105);-   4-(3,3-Difluorocyclobutyl)-2-[[4-(tetrahydropyran-4-ylmethylamino)    benzoyl]amino] thiophene-3-carboxylic acid (Compound #106);-   4-(3,3-Difluorocyclobutyl)-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #107);-   2-[[4-(2-Methoxyethylamino)benzoyl]amino]-4-(1-methylcyclopropyl)thiophene-3-carboxylic    acid (Compound #108);-   4-iso-Butyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid diethylamine salt (Compound #109);-   4-tert-Butyl-2-[[3-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #110);-   4-(1-Methylcyclopropyl)-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #111);-   2-[[4-(3-Methoxyazetidin-1-yl)benzoyl]amino]-4-(1-methylcyclopropyl)    thiophene-3-carboxylic acid (Compound #112);-   4-Isobutyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]    thiophene-3-carboxylic acid (Compound #113);-   5-Isopropyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]-4-methyl-thiophene-3-carboxylic    acid diethylamine salt (Compound #114);-   2-[[4-(3-Methoxyazetidin-1-yl)benzoyl]amino]-4-(1-methylcyclobutyl)    thiophene-3-carboxylic acid (Compound #115);-   4-tert-Butyl-2-[[4-(2-methoxyethoxy)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #116);-   4-tert-Butyl-2-[[4-[2-methoxyethyl(methyl)amino]benzoyl]    amino]thiophene-3-carboxylic acid (Compound #117);-   4-tert-Butyl-2-[[4-(tetrahydropyran-3-ylamino)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #118);-   4-tert-Butyl-2-[[4-(tetrahydropyran-3-ylmethylamino)benzoyl]amino]    thiophene-3-carboxylic acid (Compound #119);-   4-tert-Butyl-2-[[4-[methyl(tetrahydropyran-4-ylmethyl)amino]benzoyl]    amino]thiophene-3-carboxylic acid (Compound #120);-   4-tert-Butyl-2-[[2-fluoro-4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #121); and-   2-Benzamido-4-(5,6,7,8-tetrahydroquinolin-2-yl)thiophene-3-carboxylic    acid (Compound #195).

In a further preferred embodiment, the compound for use of formula (I)is selected from the group consisting of the table A.

In a particular embodiment, the viral infection is an infection by avirus selected from the group consisting of Alphaviridae, Flaviviridae,Hepadnaviridae, Herpesviridae, Orthomyxoviridae, Papovaviridae,Paramyxoviridae, Picornaviridae, Polyomaviridae, Reoviridae,Retroviridae, Rhabdoviridae, and Tobamoviruses.

In a further particular embodiment, the bacterial infection is aninfection by a bacterium selected from the group consisting ofHelicobacter pylori, Burkholderia cepacia, Pseudomonas aeruginosa,Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonasalcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Aeromonashydrophilia, Escherichia coli, Citrobacter freundii, Salmonellatyphimurium, Salmonella typhi, Salmonella paratyphi, Salmonellaenteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei,Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae,Klebsiella oxytoca, Serratia marcescens, Francisella tularensis,Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providenciaalcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacterbaumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus,Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis,Yersinia intermedia, Bordetella parapertussis, Bordetellabronchiseptica, Haemophilus parainfluenzae, Haemophilus haemolyticus,Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurellamultocida, Pasteurella haemolytica, Branhamella catarrhalis,Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borreliaburgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Listeriamonocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingelladenitrificans, Kingella indologenes, Kingella kingae, Kingella oralis,Legionella pneumophila, Moraxella bovis, Moraxella catarrhalis,Moraxella lacunata, Gardnerella vaginalis, Bacteroides fragilis,Bacteroides distasonis, Bacteroides vulgatus, Bacteroides ovalus,Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroideseggerthii, Bacteroides splanchnicus, Clostridium difficile, Clostridiumtetani, Mycobacterium species, Corynebacterium ulcerans, Streptococcusagalactiae, Gardnerella vaginitis, Streptococcus pyogenes, Enterococcusfaecalis, Enterococcus faecium, Fusobacterium nucleatum, Porphyromonasgingivalis, Vibrio vulnificus, Clostridium botulinum, Corynebacteriumdiptheriae, Staphylococcus aureus, Staphylococcus epidermidis,Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcushyicus, Staphylococcus haemolyticus, Staphylococcus hominis, andStaphylococcus saccharolyticus.

In a further particular embodiment, the cancer is selected from thegroup consisting of a breast cancer, a lung cancer, in particular NSCLC,a melanoma, a colorectal cancer, an astrocytoma cancer, a liver cancer,leukemia, in particular acute myeloid leukemia, a gastric cancer, a headand neck cancer, a cervical cancer, a pancreatic cancer, and an ovariancancer.

In a further particular embodiment, the metabolic disease is selectedfrom the group consisting of Diabetes mellitus, in particular Diabetesmellitus from NEET proteins, insulin resistance, insulin deficiency,hepatic steatosis, nonalcoholic fatty liver disease, Nonalcoholicsteatohepatitis (NASH), glucose intolerance, obesity, lipodystrophy,coronary heart disease, diabetic retinopathy, diabetic neuropathy,diabetic nephropathy, hypoglycemia, hyperglycemia, beta cell dysfunctionor hyperinsulinaemia, Wolfram syndrome, in particular Wolfram syndromefrom NEET proteins, Polycystic ovary syndrome, pyruvate dehydrogenasedeficiency, Albright hereditary osteodystrophy, cystinosis, fructoseintolerance, Walker-Warburg syndrome, hypobetalipoproteinemia, Alstrumsyndrome, and cirrhosis.

In a further particular embodiment, the cardiovascular disease isselected in the group consisting of myocardial injury, Ischemia,Ischemia reperfusion injury and hypertension.

In an additional particular embodiment, the inflammatory disease ordisorder is selected from the group consisting of Crohn disease,inflammatory bowel disease, asthma, chronic obtrusive pulmonary disease(COPD), systemic lupus erythematosus, cystic fibrosis, psoriasis,infectious arthritis, and multiple sclerosis.

In a further particular embodiment, the iron storage disorder or diseaseis selected from the group consisting of Ferroportin Deficiency,Hereditary Hemochromatosis, including Hereditary Hemochromatosis due toHFE mutations and Hereditary Hemochromatosis due to transferrin receptor2 mutations, Juvenile Hemochromatosis, including JuvenileHemochromatosis due to hepcidin mutations and Juvenile Hemochromatosisdue to hemojuvelin mutations, Iron Overload, including African IronOverload, Iron Overload secondary to atransferrinemia and Iron Overloadsecondary to aceruloplasminemia, Thalassemia, Myelodysplastic Syndromes,Congenital Dyserythropoietic Anemias, Sickle Cell Disease and otherHemoglobinopathies, Red Cell Enzyme Deficiencies and Multiple BloodTransfusions.

Another object of the invention is a new compound of formula (I) asdefined above for use as a medicine. A further object of the inventionis a pharmaceutical composition comprising a compound as defined above,and an acceptable pharmaceutical excipient. In another furtherparticular embodiment, the present invention relates to a new compoundof the present invention for use in the treatment of aging or aneurodegenerative disease or disorder.

DETAILED DESCRIPTION OF THE INVENTION Definitions

According to the present invention, the terms below have the followingmeanings:

The terms mentioned herein with prefixes such as for example C₁-C₃,C₁-C₆ or C₂-C₆ can also be used with lower numbers of carbon atoms suchas C₁-C₂, C₁-C₅, or C₂-C₅. If, for example, the term C₁-C₃ is used, itmeans that the corresponding hydrocarbon chain may comprise from 1 to 3carbon atoms, especially 1, 2 or 3 carbon atoms. If, for example, theterm C₁-C₆ is used, it means that the corresponding hydrocarbon chainmay comprise from 1 to 6 carbon atoms, especially 1, 2, 3, 4, 5 or 6carbon atoms. If, for example, the term C₂-C₆ is used, it means that thecorresponding hydrocarbon chain may comprise from 2 to 6 carbon atoms,especially 2, 3, 4, 5 or 6 carbon atoms.

The term “alkyl” refers to a saturated, linear or branched aliphaticgroup. The term “(C₁-C₃)alkyl” more specifically means methyl, ethyl,propyl, or isopropyl. The term “(C₁-C₆)alkyl” more specifically meansmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl orhexyl. In a preferred embodiment, the “alkyl” is a methyl, an ethyl, apropyl, an isopropyl, or a tert-butyl, more preferably a methyl.

The term “alkenyl” refers to an unsaturated, linear or branchedaliphatic group comprising at least one carbon-carbon double bound. Theterm “(C₂-C₆)alkenyl” more specifically means ethenyl, propenyl,isopropenyl, butenyl, isobutenyl, pentenyl, or hexenyl.

The term “alkoxy” or “alkyloxy” corresponds to the alkyl group as abovedefined bonded to the molecule by an —O— (ether) bond. (C₁-C₃)alkoxyincludes methoxy, ethoxy, propyloxy, and isopropyloxy. (C₁-C₆)alkoxyincludes methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy,isobutyloxy, tert-butyloxy, pentyloxy and hexyloxy. In a preferredembodiment, the “alkoxy” or “alkyloxy” is a methoxy.

The term “cycloalkyl” corresponds to a saturated or unsaturated mono-,bi- or tri-cyclic alkyl group comprising between 3 and 20 atoms ofcarbons. It also includes fused, bridged, or spiro-connected cycloalkylgroups. The term “cycloalkyl” includes for instance cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. The term “cycloalkyl” may alsorefer to a 5-10 membered bridged carbocyclyl such asbicyclo[2,2,1]heptanyl, bicyclo[2,2,2]octanyl, or adamantyl, preferablybicyclo[2,2,1]heptanyl. In a preferred embodiment, the “cycloalkyl” is acyclopropyl, cyclobutyl, cyclopentyl or a cyclohexyl.

The term “heterocycloalkyl” corresponds to a saturated or unsaturatedcycloalkyl group as above defined further comprising at least oneheteroatom such as nitrogen, oxygen, or sulphur atom. It also includesfused, bridged, or spiro-connected heterocycloalkyl groups.Representative heterocycloalkyl groups include, but are not limited to3-dioxolane, benzo [1,3] dioxolyl, azetidinyl, oxetanyl, pyrazolinyl,pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl,1,4-dioxanyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, piperidinyl,imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl, oxozolinyl,oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl,isothiazolinyl, isothiazolidinyl, dihydropyranyl, tetrahydropyranyl,tetrahydrofuranyl, and tetrahydrothiophenyl. The term “heterocycloalkyl”may also refer to a 5-10 membered bridged heterocyclyl such as7-oxabicyclo[2,2,1]heptanyl. In a particular embodiment, it may alsorefer to spiro-connected heterocycloalkyl groups orspiroheterocycloalkyl groups such as for instance oxetanylspiro-connected with azetidinyl or piperidinyl. In a preferredembodiment, the heterocycloalkyl group is azetidinyl, oxetanyl, pyranyl,tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl,piperazinyl, and oxetanyl spiro-connected with azetidinyl orpiperidinyl.

The term “aryl” corresponds to a mono- or bi-cyclic aromatichydrocarbons having from 6 to 12 carbon atoms. For instance, the term“aryl” includes phenyl, biphenyl, or naphthyl. In a preferredembodiment, the aryl is a phenyl.

The term “heteroaryl” as used herein corresponds to an aromatic, mono-or poly-cyclic group comprising between 5 and 14 atoms and comprising atleast one heteroatom such as nitrogen, oxygen or sulphur atom. Examplesof such mono- and poly-cyclic heteroaryl group may be: pyridinyl,thiazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl,indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl,isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, isothiazolyl,isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl,purinyl, quinolizinyl, phtalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, O-carbolinyl,phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl,isoindolinyl, oxazolidinyl, benzotriazolyl, benzoisoxazolyl, oxindolyl,benzoxazolinyl, benzothienyl, benzothiazolyl, isatinyl, dihydropyridyl,pyrimidinyl, s-triazinyl, oxazolyl, or thiofuranyl. In a preferredembodiment, the heteroaryl group is a pyridinyl, furanyl, pyrazolyl,pyrazinyl, pyrimidinyl, pyridazinyl, and isoxazolyl.

The term “fused arylheterocycloalkyl” corresponds to a bicyclic group inwhich an aryl as above defined is bounded to the heterocycloalkyl asabove defined by at least two carbons. In other terms, the aryl shares acarbon bond with the heterocycloalkyl. A fused arylheterocycloalkyl isfor instance a benzodioxole (phenyl fused to a dioxole), anisobenzofurane, or a chroman (phenyl fused to a tetrahydropyran). Theterm “fused bicycloalkyl” corresponds to a bicyclic group in which acycloalkyl as above defined is bounded to the cycloalkyl as abovedefined by at least two carbons. A fused bicycloalkyl is for instance abicyclo[4.1.0]heptanyl. The term “fused heteroarylcycloalkyl”corresponds to a bicyclic group in which an heteroaryl as above definedis bounded to the heterocycloalkyl as above defined by at least twocarbons. A fused heteroarylcycloalkyl is for instance a5,6,7,8-tetrahydroquinoline.

The term “halogen” corresponds to a fluorine, chlorine, bromine, oriodine atom, preferably a fluorine, chlorine or bromine.

The expression “substituted by at least” means that the radical issubstituted by one or several groups of the list.

The expression “optionally substituted” means, without any otherwiseprecision, optionally substituted by a hydroxy, a halogen, a(C₁-C₆)alkyl optionally substituted by at least one halogen, preferablyoptionally substituted by at least one fluorine or, a (C₁-C₆)alkoxyoptionally substituted by at least one halogen, preferably optionallysubstituted by at least one fluorine.

The “stereoisomers” are isomeric compounds that have the same molecularformula and sequence of bonded atoms, but differ in the 3D-dimensionalorientations of their atoms in space. The stereoisomers includeenantiomers, diastereoisomers, Cis-trans and E-Z isomers, conformers,and anomers. In a preferred embodiment of the invention, thestereoisomers include diastereoisomers and enantiomers. The enantiomerscompounds may be prepared from the racemate compound or the carboxylatethereof using any purification method known by a skilled person, such asLC/MS and chiral HPLC analysis methods and chiral SFC purificationmethods such as those disclosed in the examples.

The “pharmaceutically salts” include inorganic as well as organic acidssalts. Representative examples of suitable inorganic acids includehydrochloric, hydrobromic, hydroiodic, phosphoric, and the like.Representative examples of suitable organic acids include formic,acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic,citric, fumaric, maleic, methanesulfonic and the like. Further examplesof pharmaceutically inorganic or organic acid addition salts include thepharmaceutically salts listed in J. Pharm. Sci. 1977, 66, 2, and inHandbook of Pharmaceutical Salts: Properties, Selection, and Use editedby P. Heinrich Stahl and Camille G. Wermuth 2002. In a preferredembodiment, the salt is selected from the group consisting of maleate,chlorhydrate, bromhydrate, and methanesulfonate. The “pharmaceuticallysalts” also include inorganic as well as organic base salts.Representative examples of suitable inorganic bases include sodium orpotassium salt, an alkaline earth metal salt, such as a calcium ormagnesium salt, or an ammonium salt. Representative examples of suitablesalts with an organic base includes for instance a salt withmethylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine. In a preferred embodiment, the salt isselected from the group consisting of sodium and potassium salt.

As used herein, the terms “treatment”, “treat” or “treating” refer toany act intended to ameliorate the health status of patients such astherapy, prevention, prophylaxis and retardation of a disease, inparticular an infection, preferably a viral infection. In certainembodiments, such terms refer to the amelioration or eradication of thedisease, or symptoms associated with it. In other embodiments, this termrefers to minimizing the spread or worsening of the disease, resultingfrom the administration of one or more therapeutic agents to a subjectwith such a disease.

As used herein, the terms “subject”, “individual” or “patient” areinterchangeable and refer to an animal, preferably to a mammal, evenmore preferably to a human, including adult, child, newborn and human atthe prenatal stage. However, the term “subject” can also refer tonon-human animals, in particular mammals such as dogs, cats, horses,cows, pigs, sheep and non-human primates, among others.

The terms “quantity,” “amount,” and “dose” are used interchangeablyherein and may refer to an absolute quantification of a molecule.

As used herein, the terms “active principle”, “active ingredient” and“active pharmaceutical ingredient” are equivalent and refers to acomponent of a pharmaceutical composition having a therapeutic effect.

As used herein, the term “therapeutic effect” refers to an effectinduced by an active ingredient, or a pharmaceutical compositionaccording to the invention, capable to prevent or to delay theappearance or development of a disease or disorder, or to cure or toattenuate the effects of a disease or disorder.

As used herein, the term “effective amount” refers to a quantity of anactive ingredient or of a pharmaceutical composition which prevents,removes or reduces the deleterious effects of the disease, particularlyinfectious disease. It is obvious that the quantity to be administeredcan be adapted by the man skilled in the art according to the subject tobe treated, to the nature of the disease, etc. In particular, doses andregimen of administration may be function of the nature, of the stageand of the severity of the disease to be treated, as well as of theweight, the age and the global health of the subject to be treated, aswell as of the judgment of the doctor.

As used herein, the term “excipient or pharmaceutically acceptablecarrier” refers to any ingredient except active ingredients that ispresent in a pharmaceutical composition. Its addition may be aimed toconfer a particular consistency or other physical or gustativeproperties to the final product. An excipient or pharmaceuticallyacceptable carrier must be devoid of any interaction, in particularchemical, with the active ingredients.

The term “modulator”, as used herein, refers to a molecule, a chemicalor a substance targeting, added, applied or active to another, tomodulate a reaction or to prevent an unwanted change. As used herein,the term “modulator” refers to any molecule or compound having an effecton Fe—S cluster binding by the NEET protein. The “modulator” as usedherein may be either a stabiliser or a destabiliser. The term“stabiliser” as used herein refers to any compound, chemical, orsubstance able to stabilize the Fe—S cluster binding the NEET protein.Particularly, a stabiliser reduces the off-rate of iron (Fe) or slowsthe release of bound Fe—S. In a preferred embodiment, a compound of theinvention as disclosed herein may be a “stabiliser” when it is able toincrease the time needed to reach 50% Fe—S cluster bound loss by morethan 25%. The term “destabiliser” as used herein refers to any compound,chemical, or substance able to destabilize the Fe—S cluster binding theNEET protein. Particularly, a destabiliser enhances the off-rate of iron(Fe). In a preferred embodiment, a compound of the invention asdisclosed herein may be a “destabiliser” when it is able to decrease thetime needed to reach 50% Fe—S cluster bound loss by more than 25%. Theeffect of the modulator can be determined by the protocol detailed inExample B3.

Compounds

Compounds for Therapeutic Applications According to the Invention

As illustrated by examples, the inventors have demonstrated an antiviraleffect for the compounds of formula (I). Accordingly, the compounds canbe useful as an antiviral drug, i.e., for treating a viral infection.The compounds can also be useful for treating a bacterial infection,cancer, a metabolic disease, a cardiovascular disease, an inflammatorydisorder, and iron storage disease/disorder.

Accordingly, the present invention relates to a compound for useaccording to the present invention, said compound having the formula(I):

-   -   wherein:        -   R₁ represents:            -   a 3-10 membered ring, saturated or unsaturated selected                in the group consisting of an aryl, a heteroaryl, a                cycloalkyl, a heterocycloalkyl, a fused                arylheterocycloalkyl, a fused heteroarylcycloalkyl, a                fused bicycloalkyl, and a bridged carbocyclyl, said 3-10                membered ring is optionally substituted by at least one                radical selected in the group consisting of:                -   a halogen,                -   a (C₁-C₆)alkyl or a (C₁-C₆)alkyloxy optionally                    substituted by at least one halogen, preferably                    optionally substituted by at least one fluorine, and                -   a hydroxy,                -   a —CO—R₆ or a —CO₂R₆ with R₆ being a hydrogen or a                    (C₁-C₆)alkyl, and                -   an optionally substituted aryl, or            -   a (C₁-C₆)alkyl, optionally substituted by at least one                radical selected in the group consisting of:                -   a halogen, preferably a fluorine,                -   a (C₁-C₆)alkyloxy optionally substituted by at least                    one halogen, preferably optionally substituted by at                    least one fluorine, and                -   a 5-10 membered ring as defined above, and            -   a hydrogen;        -   R₂ represents:            -   a hydrogen,            -   a halogen,            -   a (C₁-C₆)alkyl optionally substituted by at least one                halogen, preferably optionally substituted by at least                one fluorine,            -   an optionally substituted aryl, or            -   an optionally substituted cycloalkyl;        -   R₃ represents:            -   a 5-10 membered ring, saturated or unsaturated selected                in the group consisting of:                -   an aryl optionally fused to a heterocycloalkyl,                    preferably selected from the group consisting of a                    dioxole, a morpholine, a dioxane, a tetrahydropyran,                    and a tetrahydrofuran,                -   a heteroaryl,                -   a cycloalkyl,                -   a heterocycloalkyl, and                -   a 5-10 membered bridged carbocyclyl or heterocyclyl,                -   said 5-10 membered ring is optionally substituted by                    at least one radical selected in the group                    consisting of:                -    a halogen,                -    a (C₁-C₆)alkyl optionally substituted by at least                    one halogen, preferably optionally substituted by at                    least one fluorine, or by an optionally bridged                    heterocycloalkyl optionally substituted by a                    (C₁-C₆)alkyl,                -    a —NH—(C₁-C₆)alkyl or a —N—((C₁-C₆)alkyl)₂,                    optionally substituted by at least one radical                    selected in the group consisting of a                    heterocycloalkyl, a cycloalkyl, a hydroxyl, a                    thiacycloalkyl-1,1dioxide and a (C₁-C₆)alkyloxy,                -    a —NH-heterocycloalkyl, a —NH-cycloalkyl, a                    —N((C₁-C₆)alkyl)-heterocycloalkyl, or a                    —NH((C₁-C₆)alkyl)-thiacycloalkyl-1,1dioxide,                    optionally substituted by a hydroxyl, a                    (C₁-C₆)alkyl, a (C₁-C₆)alkyloxy or a —CO—R₆ with R₆                    being a hydrogen or a (C₁-C₆)alkyl,                -    a hydroxy, a —CN, a —CO—R₆ or a —CO₂R₆ with R₆                    being a hydrogen or a (C₁-C₆)alkyl,                -    a (C₁-C₆)alkyloxy optionally substituted by at                    least one radical selected in the group consisting                    of a halogen, preferably a fluorine, a hydroxy, a                    (C₁-C₆)alkyloxy, a —NR₇R₈ with R₇ and R₈ are                    independently a hydrogen or a (C₁-C₆)alkyl, a                    —NHCOR₉, a —NHCO₂R₉, with R₉ being a (C₁-C₆)alkyl, a                    —CO₂R₆ with R₆ being a hydrogen or a (C₁-C₆)alkyl,                    and a heterocycle,                -    a —NHCOR₉, a-NHCO₂R₉, or a —SO₂R₉, with R₉ being a                    (C₁-C₆)alkyl, and                -    a heterocycloalkyl, a bridged heterocycloalkyl, a                    heterocycloalkyloxy, a cycloalkyloxy, a                    thiaheterocycloalkyl-1,1-dioxide or a                    spiroheterocycloalkyl, optionally substituted by a                    (C₁-C₆)alkyl, a (C₁-C₆)alkyloxy, a hydroxy, a                    ketone, a halogen or a (C₁-C₆)alkyl optionally                    substituted by a (C₁-C₆)alkyloxy; or            -   a (C₁-C₆)alkyl or a (C₂-C₆)alkenyl, optionally                substituted by a 5-10 membered ring as defined above or                a —CO₂R₆ with R₆ being a hydrogen or a (C₁-C₆)alkyl;        -   R₄ represents:            -   a —CO₂R₁₀ with R₁₀ being a hydrogen or a (C₁-C₆)alkyl;                and            -   a 5-10 membered ring, saturated or unsaturated selected                in the group consisting of an aryl, a heteroaryl, a                cycloalkyl, and a heterocycloalkyl, said 5-10 membered                ring is optionally substituted by a hydroxy, a halogen,                or a (C₁-C₆)alkyl optionally substituted by at least one                halogen, preferably optionally substituted by at least                one fluorine; and        -   R₅ represents:            -   a hydrogen, or            -   a (C₁-C₆)alkyl optionally substituted by at least one                halogen, preferably optionally substituted by at least                one fluorine,    -   and the stereoisomers, and the pharmaceutical salts thereof.

In a particular embodiment of formula (I), R₁ represents:

-   -   a fused arylheterocycloalkyl, a fused heteroarylcycloalkyl, a        fused bicycloalkyl, a cycloalkyl or an aryl, optionally        substituted by at least one radical selected in the group        consisting of:        -   a halogen,        -   a (C₁-C₆)alkyl optionally substituted by at least one            halogen, preferably optionally substituted by at least one            fluorine,        -   a (C₁-C₆)alkyloxy optionally substituted by at least one            halogen, preferably optionally substituted by at least one            fluorine, and        -   an optionally substituted phenyl,    -   a bridged carbocyclyl, and    -   a (C₁-C₆)alkyl optionally substituted by at least one halogen,        preferably optionally substituted by at least one fluorine.

In a particular embodiment R₁ represents:

-   -   a phenyl fused to a tetrahydropyran (chroman), a fused        bicycloalkyl,    -   a cycloalkyl, optionally substituted by at least one radical        selected in the group consisting of:        -   a halogen, preferably a fluorine,        -   a (C₁-C₆)alkyl optionally substituted by at least one            halogen, preferably optionally substituted by at least one            fluorine, and        -   an optionally substituted phenyl,    -   an aryl, preferably a phenyl, optionally substituted by at least        one radical selected in the group consisting of:        -   a halogen, preferably a chlorine or a fluorine,        -   a (C₁-C₆)alkyl optionally substituted by at least one            halogen, preferably optionally substituted by at least one            fluorine, and        -   a (C₁-C₆)alkyloxy optionally substituted by at least one            halogen, preferably optionally substituted by at least one            fluorine, preferably a methoxy,    -   a bridged carbocyclyl, preferably a bridged cyclohexyl, or    -   a (C₁-C₆)alkyl optionally substituted by at least one halogen,        preferably optionally substituted by at least one fluorine.

In a particular aspect, R₁ is a fused arylheterocycloalkyl, preferably achroman, or a fused bicycloalkyl, preferably a bicyclo[4.1.0]heptanyl,more preferably a chroman, or a fused heteroarylcycloalkyl, preferably atetrahydroquinoline.

In a further particular aspect, R₁ is a cycloalkyl, preferably acyclopropyl, a cyclobutyl, a cyclopentyl, a cyclohexyl, more preferablya cyclopropyl, cyclopentyl or a cyclohexyl, optionally substituted by atleast one radical selected in the group consisting of a halogen,preferably a fluorine, a (C₁-C₆)alkyl, preferably a methyl, atert-butyl, and a phenyl. In a particular embodiment, R₁ is a cyclobutylsubstituted by two fluorine atoms, preferably said two fluorine atomsare bounded on the same carbon of the cyclobutyl. In a furtherparticular embodiment, R₁ is a cyclopropyl substituted by one, two,three or four methyl or a cyclohexyl substituted by a tert-butyl. In afurther particular embodiment, R₁ is a cyclobutyl substituted by aphenyl.

In a further particular aspect, R₁ is an aryl, preferably a phenyl,optionally substituted by at least one radical selected in the groupconsisting of a halogen, preferably a chlorine and/or a fluorine, a(C₁-C₆)alkyl, preferably a methyl, optionally substituted by at leastone halogen, preferably optionally substituted by at least one fluorine(—CH₂F, —CHF₂, —CF₃), and a (C₁-C₆)alkyloxy, preferably a methoxy.

In a further particular aspect, R₁ is a bridged carbocyclyl, preferablya bicyclo[2,2,1]heptanyl.

In a further particular aspect, R₁ is a (C₁-C₆)alkyl optionallysubstituted by at least one halogen, preferably optionally substitutedby at least one fluorine, preferably a methyl, an isopropyl, an isobutylor a tert-butyl.

In a preferred embodiment, R₁ is a radical selected in the groupconsisting of:

In a further particular embodiment, R₂ represents a hydrogen, a halogen,preferably a chlorine, a (C₁-C₆)alkyl optionally substituted by at leastone halogen, preferably optionally substituted by at least one fluorine,preferably a methyl or an isopropyl, an optionally substituted(C₃-C₆)cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, more preferably cyclopropyl or cyclohexyl, or an optionallysubstituted aryl, preferably a phenyl. More preferably R₂ is a hydrogen,a chlorine, a methyl, an isopropyl, a phenyl, a cyclohexyl. In a moreparticular embodiment, R₂ is a Hydrogen.

In a preferred embodiment, R₁ is a fused arylheterocycloalkyl, acycloalkyl, or an aryl as above defined and R₂ is a hydrogen, achlorine, or a methyl.

In another embodiment, R₁ is a hydrogen or a (C₁-C₆)alkyl optionallysubstituted by at least one halogen, preferably optionally substitutedby at least one fluorine, preferably a methyl, an isopropyl, an isobutylor a tert-butyl, and R₂ is a hydrogen, a halogen, preferably a chlorine,a (C₁-C₆)alkyl optionally substituted by at least one halogen,preferably optionally substituted by at least one fluorine, preferably amethyl or an isopropyl, an optionally substituted (C₃-C₆)cycloalkyl,preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, morepreferably cyclopropyl or cyclohexyl, or an optionally substituted aryl,preferably a phenyl.

According to the present invention, R₃ represents:

-   -   a 5-10 membered ring, saturated or unsaturated selected in the        group consisting of:        -   an aryl optionally fused to a heterocycloalkyl, preferably            selected from the group consisting of a dioxole, a            morpholine, a dioxane, a tetrahydropyran, and a            tetrahydrofuran,        -   a heteroaryl,        -   a cycloalkyl,        -   a heterocycloalkyl, and        -   a 5-10 membered bridged carbocyclyl or heterocyclyl, said            5-10 membered ring is optionally substituted by at least one            radical selected in the group consisting of:            -   a halogen,            -   a (C₁-C₆)alkyl optionally substituted by at least one                halogen, preferably optionally substituted by at least                one fluorine, or by an optionally bridged                heterocycloalkyl optionally substituted by a                (C₁-C₆)alkyl,            -   a —NH—(C₁-C₆)alkyl or a —N—((C₁-C₆)alkyl)₂, optionally                substituted by at least one radical selected in the                group consisting of a heterocycloalkyl, a cycloalkyl, a                hydroxyl, a thiacycloalkyl-1,1dioxide and a                (C₁-C₆)alkyloxy,            -   a —NH-heterocycloalkyl, a —NH-cycloalkyl, a                —N((C₁-C₆)alkyl)-heterocycloalkyl, or a                —NH((C₁-C₆)alkyl)-thiacycloalkyl-1,1dioxide, optionally                substituted by a hydroxyl, a (C₁-C₆)alkyl, a                (C₁-C₆)alkyloxy or a —CO—R₆ with R₆ being a hydrogen or                a (C₁-C₆)alkyl,            -   a hydroxy, a —CN, a —CO—R₆ or a —CO₂R₆ with R₆ being a                hydrogen or a (C₁-C₆)alkyl,            -   a (C₁-C₆)alkyloxy optionally substituted by at least one                radical selected in the group consisting of a halogen,                preferably a fluorine, a hydroxy, a (C₁-C₆)alkyloxy, a                —NR₇R₈ with R₇ and R₈ are independently a hydrogen or a                (C₁-C₆)alkyl, a —NHCOR₉, a —NHCO₂R₉, with R₉ being a                (C₁-C₆)alkyl, a —CO₂R₆ with R₆ being a hydrogen or a                (C₁-C₆)alkyl, and a heterocycle,            -   a —NHCOR₉, a —NHCO₂R₉, or a —SO₂R₉, with R₉ being a                (C₁-C₆)alkyl, and            -   a heterocycloalkyl, a bridged heterocycloalkyl, a                heterocycloalkyloxy, a cycloalkyloxy, a                thiaheterocycloalkyl-1,1-dioxide or a                spiroheterocycloalkyl, optionally substituted by a                (C₁-C₆)alkyl, a (C₁-C₆)alkyloxy, a hydroxy, a ketone, a                halogen or a (C₁-C₆)alkyl optionally substituted by a                (C₁-C₆)alkyloxy, or    -   a (C₁-C₆)alkyl or a (C₂-C₆)alkenyl, optionally substituted by a        5-10 membered ring as defined above or a —CO₂R₆ with R₆ being a        hydrogen or a (C₁-C₆)alkyl,        and R₁, R₂, R₄, and R₅ are such as defined herein.

In a particular embodiment, R₃ represents a phenyl, a pyridinyl or apyrimidinyl, preferably a phenyl, optionally substituted by at least oneradical selected in the group consisting of:

-   -   a halogen, preferably a fluorine or a chlorine,    -   a (C₁-C₆)alkyl optionally substituted by at least one halogen,        preferably optionally substituted by at least one fluorine, or        by a (C₁-C₆)alkyloxy,    -   a —NH—(C₁-C₆)alkyl or a —N—((C₁-C₆)alkyl)₂, optionally        substituted by a heterocycloalkyl or a (C₁-C₆)alkyloxy,    -   a —NH-heterocycloalkyl, a —NH-cycloalkyl, or a        —N((C₁-C₆)alkyl)-heterocycloalkyl, optionally substituted by a        (C₁-C₆)alkyloxy or a —CO—R₆ with R₆ being a hydrogen or a        (C₁-C₆)alkyl,    -   a hydroxy, a —CN, a —CO—R₆ or a —CO₂R₆ with R₆ being a hydrogen        or a (C₁-C₆)alkyl,    -   a (C₁-C₆)alkyloxy optionally substituted by at least one radical        selected in the group consisting of a halogen, preferably a        fluorine, a hydroxy, a (C₁-C₆)alkyloxy, a —NR₇R₈ with R₇ and R₈        are independently a hydrogen or a (C₁-C₆)alkyl, a —NHCOR₉, a        —NHCO₂R₉, with R₉ being a (C₁-C₆)alkyl, a —CO₂R₆ with R₆ being a        hydrogen or a (C₁-C₆)alkyl, and a heterocycle,    -   a —NHCOR₉, a —NHCO₂R₉ or a —SO₂R₉ with R₉ being a (C₁-C₆)alkyl,        and    -   a heterocycloalkyl, a bridged heterocycloalkyl, a cycloalkoxy, a        heterocycloalkyloxy or a spiroheterocycloalkyl, optionally        substituted by a (C₁-C₆)alkyloxy, a hydroxy, a halogen or a        (C₁-C₆)alkyl optionally substituted by a (C₁-C₆)alkyloxy.

In a preferred embodiment, R₃ is a phenyl, i.e. an unsubstituted phenyl.In an alternative embodiment, R₃ is a pyridinyl or a pyrimidinyl.

In one aspect, R₃ is a phenyl, a pyridinyl or a pyrimidinyl, preferablya phenyl, substituted by at least one radical selected in the groupconsisting of a halogen, preferably a chlorine, a fluorine, or abromine, a methyl, a difluoromethyl, a trifluoromethyl, a hydroxy, acyano (—CN), a methoxy, a difluoromethoxy, a trifluoromethoxy, anisopropyloxy, a tertiobutyloxy, a cyclobutyloxy, an ethoxy, propyloxy orbutyloxy substituted by a methoxy (—O—(CH₂)₂₋₄—OCH₃) or by a hydroxy(—O—(CH₂)₂—OH), a —SO₂—CH₃, and a —NHCOR₇ with R₇ being a methyl. Inanother aspect, R₃ is a phenyl, a pyridinyl or a pyrimidinyl, preferablya phenyl, substituted by an optionally bridged heterocycle, preferablyan azetidinyl, a morpholinyl, a bridged morpholinyl, a piperidinyl, apiperazinyl, a tetrahydropyranyl, a pyrrolidine-2-one, a1,1-dioxo-1,2-thiazolidin, or a azetidinyl or piperidinylspiro-connected with an oxetanyl, more preferably an azetidinyl, atetrahydropyranyl, a morpholinyl, a 6-oxa-3-azabicyclo[3.1.1]heptane, ora 8 oxa-3-azabicyclo [3.2.1]octane, said heterocycle being optionallysubstituted by a methoxy, an ethoxy, a hydroxy, a methyl optionallysubstituted by a methoxy, a halogen, preferably a fluorine. In a veryparticular aspect, R₃ is a phenyl, a pyridinyl or a pyrimidinyl,preferably a phenyl, substituted by an azetidinyl optionally substitutedby a methoxy, or an optionally bridged morpholinyl (e.g., linked to thephenyl by the nitrogen) optionally substituted by one or two methyl. Inanother very particular aspect, R₃ is a phenyl, a pyridinyl or apyrimidinyl, preferably a phenyl, substituted by a bridged heterocycle,preferably, a 6-oxa-3-azabicyclo[3.1.1]heptane, and a 8 oxa-3-azabicyclo[3.2.1]octane.

In a further aspect, R₃ is a phenyl, a pyridinyl or a pyrimidinyl,preferably a phenyl, substituted by a (C₁-C₆)alkyl substituted by aheterocycle, preferably a —CH₂-morpholinyl.

In a further aspect, R₃ is a phenyl, a pyridinyl or a pyrimidinyl,preferably a phenyl, substituted by a —NH—(C₁-C₆)alkyl or a—N—((C₁-C₆)alkyl)₂, optionally substituted by a heterocycloalkyl, acycloalkyl, a hydroxyl, a thiacycloalkyl-1,1-dioxide, or a(C₁-C₆)alkyloxy, preferably a phenyl, a pyridinyl or a pyrimidinyl,preferably a phenyl, substituted by a —NH—CH₂-azetidinyl, a—NH—(CH₂)₂—OCH₃, a —NH—(CH₂)₃—OCH₃, a —NH—(CH₂)₄—OCH₃, a—NH—CH₂-tetrahydropyranyl, a —N(CH₃)—CH₂-tetrahydropyranyl, a—NH—(CH₂)-cyclohexyl, a —NH—CH(CH₂OH)-tetrahydropyranyl, a—NH—CH₂-hydroxytetrahydropyranyl, a —NH—(CH₂)₄—OH, —N(CH₃)—(CH₂)₂—OCH₃,a —N(CH₃)—CH₂-tetrahydropyranyl and NH—CH₂-thiacycloalkyl-1,1-dioxide.

In a further aspect, R₃ is a phenyl, a pyridinyl or a pyrimidinyl,preferably a phenyl, substituted by a —NH-heterocycloalkyl, a—NH-cycloalkyl, a —N((C₁-C₆)alkyl)-heterocycloalkyl or—NH((C₁-C₆)alkyl)-thiacycloalkyl-1,1dioxide, optionally substituted by a(C₁-C₆)alkyl, a hydroxyl, a (C₁-C₆)alkyloxy or a —CO—R₆ with R₆ being ahydrogen or a (C₁-C₆)alkyl, preferably a —NH-tetrahydropyranyl, a—NH-tetrahydrofuranyl, a —NH-oxetanyl, a —NH-piperidinyl optionallysubstituted by a —CO—CH₃, a —NH-azetidinyl optionally substituted by a—CO—CH₃, a —N(CH₃)-azetidinyl optionally substituted by a —CO—CH₃, a—N(CH₃)-tetrahydropyranyl, and a —NH-cyclohexyl, more preferably a —NH—tetrahydropyranyl.

In a further preferred embodiment, R₃ is a phenyl, a pyridinyl or apyrimidinyl, preferably a phenyl, substituted by a (C₁-C₆)alkyloxy,preferably a methoxy, an ethoxy, a propoxy, a butoxy, a pentoxy, adifluoromethoxy, a trifluoromethoxy, optionally substituted by a radicalselected in the group consisting of a hydroxyl, a methoxy, a —NHCO₂R₉,with R₉ being a methyl, a —NR₇R₈ with R₇ and R₈ are a hydrogen, a —CO₂R₆with R₆ being a methyl, and a heterocycle, preferably atetrahydropyranyl or a oxetanyl, preferably optionally substituted by agroup consisting of a hydroxyl, a methoxy, a tetrahydropyranyl and aoxetanyl. In a further aspect, R₃ is a phenyl, a pyridinyl or apyrimidinyl, preferably a phenyl, substituted by a heterocycloalkyloxy,preferably a tetrahydropyranyloxy or by a cycloalkyloxy, preferably acyclobutyloxy.

In a further particular aspect, R₃ is an aryl fused to a dioxole,preferably a benzo[1,3]dioxole optionally substituted by at least onefluorine, an aryl fused to a morpholine, preferably abenzo[1,3]morpholine optionally substituted by a methyl, an aryl fusedto a dioxane, an aryl fused to a tetrahydrofuran optionally substitutedby at least one methyl, an aryl fused to a tetrahydropyran. Preferably,the aryl is a phenyl.

In a further particular aspect, R₃ is a heteroaryl, preferably apyridinyl, a pyrimidinyl, a furanyl, a pyrazolyl, or a benzoisoxazolyl,said heteroaryl being optionally substituted by at least one radical asdisclosed above, for instance selected in the group consisting of amethoxy, a methyl, and a morpholinyl.

In a more particular aspect, R₃ is a phenyl substituted by amorpholinyl, a —NH— tetrahydropyranyl, a —NH—(C₁-C₆)alkyl, optionallysubstituted by a tetrahydropyranyl or a (C₁-C₆)alkyloxy, a—N—((C₁-C₆)alkyl)₂, optionally substituted by a tetrahydropyranyl or a(C₁-C₆)alkyloxy, an azetidinyl optionally substituted by a(C₁-C₆)alkyloxy, a (C₁-C₆)alkyloxy, optionally substituted by at leastone halogen, preferably optionally substituted by at least one fluorine,or a (C₁-C₆)alkyloxy, a halogen, preferably a fluorine, or a(C₁-C₆)alkyl optionally substituted by at least one halogen, preferablyoptionally substituted by at least one fluorine.

In a more particular aspect, R₃ is a phenyl substituted by amorpholinyl, a —NH— tetrahydropyranyl, a —NH—CH₂-tetrahydropyranyl, a—NH—(CH₂)₂—OCH₃, a —N(CH₃)—CH₂-tetrahydropyranyl, a —N(CH₃)—(CH₂)₂—OCH₃,an azetidinyl substituted by a methoxy or an ethoxy, a —O—(CH₂)₂—OCH₃,—O—CHF₂, a methyl (CH₃), or at least one methoxy (—OCH₃).

In a preferred aspect, R₃ is a radical selected in the group consistingof:

In a particular embodiment, R₄ represents:

-   -   a —CO₂R₁₀ with R₁₀ being a hydrogen or a (C₁-C₆)alkyl; or    -   a 5-10 membered ring, saturated or unsaturated selected in the        group consisting of an aryl, a heteroaryl, a cycloalkyl, and a        heterocycloalkyl, said 5-10 membered ring is optionally        substituted by a hydroxy, a halogen, or a (C₁-C₆)alkyl        optionally substituted by at least one halogen, preferably        optionally substituted by at least one fluorine,        and R₁, R₂, R₃, and R₅ are such as defined herein are such as        defined herein.

In one embodiment, the 5-10 membered ring is selected so as to be an(bio)isostere of a carboxyl group.

In a preferred embodiment, R₄ represents a heteroaryl, preferably atetrazolyl, an aryl optionally substituted by a hydroxy, preferably aphenyl substituted by a hydroxy, or a —CO₂R₁₀ with R₁₀ being a hydrogenor a (C₁-C₆)alkyl, preferably an ethyl. In a more preferred embodiment,R₁₀ represents a —CO₂R₁₀ with R₁₀ being a hydrogen, i.e. —COOH.

In a particularly preferred embodiment, R₄ is —COOH and R₁, R₂, R₃, andR₅ are such as defined herein are such as defined herein.

In a particular embodiment, R₅ represents a hydrogen.

In a preferred embodiment,

-   -   R₁ represents a cyclobutyl, a cyclopentyl or a tert-butyl;    -   R₂ represents a hydrogen or a chlorine;    -   R₃ represents radical selected in the group consisting of:        -   a phenyl or a phenyl substituted by an heterocycle,            preferably a morpholinyl or an azetidinyl optionally            substituted by a (C₁-C₆)alkyloxy,        -   a —NH—(C₁-C₆)alkyl-tetrahydropyranyl, preferably a            —NH—CH₂-tetrahydropyranyl,        -   a N(—(C₁-C₆)alkyl)₂ substituted by a methoxy, preferably a            —N(CH₃)—(CH₂)₂—OCH₃, and        -   a (C₁-C₆)alkyloxy substituted by a (C₁-C₆)alkyloxy,            preferably a —O—(CH₂)₂—O—CH₃;    -   R₄ is —COOH; and    -   R₅ is a hydrogen.

In a further preferred embodiment, the compound for use according to thepresent invention is selected in the group consisting of compounds ofthe table A below:

TABLE A

  Compound #18

  Compound #10

  Compound #4

  Compound #2

  Compound #15

  Compound #9

  Compound #6

  Compound #5

  Compound #12

  Compound #1

  Compound #20

  Compound #24

  Compound #13

  Compound #11

  Compound #23

  Compound #14

  Compound #22

  Compound #21

  Compound #25

  Compound #26

  Compound #27

  Compound #28

  Compound #29

  Compound #30

  Compound #31

  Compound #32

  Compound #33

  Compound #34

  Compound #35

  Compound #36

  Compound #37

  Compound #38

  Compound #39

  Compound #40

  Compound #41

  Compound #42

  Compound #43

  Compound #44

  Compound #45

  Compound #46

  Compound #48

  Compound #50

  Compound #54

  Compound #59

  Compound #60

  Compound #61

  Compound #62

  Compound #63

  Compound #66

  Compound #71

  Compound #72

  Compound #73

  Compound #74

  Compound #75

  Compound #76

  Compound #77

  Compound #78

  Compound #79

  Compound #80

  Compound #81

  Compound #82

  Compound #83

  Compound #84

  Compound #85

  Compound #87

  Compound #88

  Compound #90

  Compound #91

  Compound #92

  Compound #95

  Compound #96

  Compound #97

  Compound #98

  Compound #99

  Compound #100

  Compound #102

  Compound #103

  Compound #104

  Compound #105

  Compound #106

  Compound #107

  Compound #108

  Compound #109

  Compound #110

  Compound #111

  Compound #112

  Compound #113

  Compound #114

  Compound #115

  Compound #116

  Compound #117

  Compound #118

  Compound #119

  Compound #120

  Compound #121

  Compound #195

New Compounds of the Invention

The inventors have also provided new compounds and the stereoisomers andthe pharmaceutical salts thereof of formula (I):

-   -   wherein:        -   R₁ represents:            -   a 3-10 membered ring, saturated or unsaturated selected                in the group consisting of an aryl, a cycloalkyl, a                heterocycloalkyl, a fused arylheterocycloalkyl, a fused                heteroarylcycloalkyl, a fused bicycloalkyl, and a                bridged carbocyclyl, said 3-10 membered ring is                optionally substituted by at least one radical selected                in the group consisting of:                -   a halogen,                -   a (C₁-C₆)alkyl or a (C₁-C₆)alkyloxy optionally                    substituted by at least one halogen, preferably                    optionally substituted by at least one fluorine, and                -   a hydroxy,                -   a —CO—R₆ or a —CO₂R₆ with R₆ being a hydrogen or a                    (C₁-C₆)alkyl, and                -   an optionally substituted aryl, or            -   a (C₁-C₆)alkyl, optionally substituted by at least one                radical selected in the group consisting of:                -   a halogen, preferably a fluorine,                -   a (C₁-C₆)alkyloxy optionally substituted by at least                    one halogen, preferably optionally substituted by at                    least one fluorine, and                -   a 3-10 membered ring as defined above;        -   R₂ represents:            -   a hydrogen,            -   a halogen,            -   a (C₁-C₆)alkyl optionally substituted by at least one                halogen, preferably optionally substituted by at least                one fluorine,            -   an optionally substituted aryl, or            -   an optionally substituted cycloalkyl;        -   R₃ represents:            -   a 5-10 membered ring, saturated or unsaturated selected                in the group consisting of:                -   an aryl optionally fused to a heterocycloalkyl,                    preferably selected from the group consisting of a                    dioxole, a morpholine, a dioxane, a tetrahydropyran,                    and a tetrahydrofuran,                -   a heteroaryl,                -   a cycloalkyl,                -   a heterocycloalkyl, and                -   a 5-10 membered bridged carbocyclyl or heterocyclyl,                -   said 5-10 membered ring is optionally substituted by                    at least one radical selected in the group                    consisting of:                -    a halogen,                -    a (C₁-C₆)alkyl optionally substituted by at least                    one halogen, preferably optionally substituted by at                    least one fluorine, or by an optionally bridged                    heterocycloalkyl optionally substituted by a                    (C₁-C₆)alkyl,                -    a —NH—(C₁-C₆)alkyl or a —N—((C₁-C₆)alkyl)₂,                    optionally substituted by at least one radical                    selected in the group consisting of a                    heterocycloalkyl, a cycloalkyl, a hydroxyl, a                    thiacycloalkyl-1,1dioxide and a (C₁-C₆)alkyloxy,                -    a —NH-heterocycloalkyl, a —NH-cycloalkyl, a                    —N((C₁-C₆)alkyl)-heterocycloalkyl, or a                    —NH((C₁-C₆)alkyl)-thiacycloalkyl-1,1dioxide,                    optionally substituted by a hydroxyl, a                    (C₁-C₆)alkyl, a (C₁-C₆)alkyloxy or a —CO—R₆ with R₆                    being a hydrogen or a (C₁-C₆)alkyl,                -    a hydroxy, a —CN, a —CO—R₆ or a —CO₂R₆ with R₆                    being a hydrogen or a (C₁-C₆)alkyl,                -    a (C₁-C₆)alkyloxy optionally substituted by at                    least one radical selected in the group consisting                    of a halogen, preferably a fluorine, a hydroxy, a                    (C₁-C₆)alkyloxy, a —NR₇R₈ with R₇ and R₈ are                    independently a hydrogen or a (C₁-C₆)alkyl, a                    —NHCOR₉, a —NHCO₂R₉, with R₉ being a (C₁-C₆)alkyl, a                    —CO₂R₆ with R₆ being a hydrogen or a (C₁-C₆)alkyl,                    and a heterocycle,                -    a —NHCOR₉, a —NHCO₂R₉, or a —SO₂R₉, with R₉ being a                    (C₁-C₆)alkyl, and                -    a heterocycloalkyl, a bridged heterocycloalkyl, a                    heterocycloalkyloxy, a cycloalkyloxy, a                    thiaheterocycloalkyl-1,1-dioxide or a                    spiroheterocycloalkyl, optionally substituted by a                    (C₁-C₆)alkyl, a (C₁-C₆)alkyloxy, a hydroxy, a                    ketone, a halogen or a (C₁-C₆)alkyl optionally                    substituted by a (C₁-C₆)alkyloxy, or            -   a (C₁-C₆)alkyl or a (C₂-C₆)alkenyl, optionally                substituted by a 5-10 membered ring as defined above or                a —CO₂R₆ with R₆ being a hydrogen or a (C₁-C₆)alkyl;        -   R₄ represents:            -   a —CO₂R₁₀ with R₁₀ being a hydrogen or a (C₁-C₆)alkyl;                and        -   R₅ represents:            -   a hydrogen, or            -   a (C₁-C₆)alkyl optionally substituted by at least one                halogen, preferably optionally substituted by at least                one fluorine;    -   with the proviso that when R₁ is a phenyl or a phenyl        substituted by a bromine, a methyl, a methoxy or an ethoxy, then        R₃ is not a phenyl substituted by a tert-butyl; and    -   with the proviso that when R₁ is a hydrogen, then R₃ is a 5-10        membered ring and R₂ is an optionally substituted aryl or an        optionally substituted cycloalkyl;    -   and the stereoisomers, and the pharmaceutical salts thereof.

An object of the invention is thus a compound and the stereoisomers andthe pharmaceutical salts thereof of formula (I):

-   -   wherein:    -   R₁, R₂, R₃, R₄, and R₅ are such as above defined including all        the particular aspects;    -   with the proviso that when R₁ is a phenyl or a phenyl        substituted by a bromine, a methyl, a methoxy or an ethoxy, then        R₃ is not a phenyl substituted by a tert-butyl; and    -   with the proviso that when R₁ is a hydrogen, then R₃ is a 5-10        membered ring and R₂ is an optionally substituted aryl or an        optionally substituted cycloalkyl.

In an embodiment, R₁ is not a hydrogen.

In one embodiment, the compound is such as, when R₁ is an aryloptionally substituted by at least one radical as defined above, then R₃is not a phenyl substituted by a tert-butyl.

More particularly, in one embodiment, the compounds of formula (I) aresuch as:

-   -   when R₁ is an aryl optionally substituted by at least one        radical selected in the group consisting of:        -   a halogen,        -   a (C₁-C₆)alkyl or a (C₁-C₆)alkyloxy optionally substituted            by at least one halogen, preferably optionally substituted            by at least one fluorine, and        -   a hydroxy,        -   a —CO—R₆ or a —CO₂R₆ with R₆ being a hydrogen or a            (C₁-C₆)alkyl, and        -   an aryl,    -   then R₃ is not a phenyl substituted by a tert-butyl.

In another embodiment, the compounds of formula (I) are such as:

-   -   when R₁ is an aryl optionally substituted by at least one        radical selected in the group consisting of:        -   a halogen, preferably a bromine, and        -   a (C₁-C₆)alkyl, preferably a methyl, or a (C₁-C₆)alkyloxy,            preferably a methoxy, or an ethoxy,    -   then R₃ is not a phenyl substituted by a tert-butyl.

In a further more preferred embodiment, a compound of formula (I) isselected in the group consisting of compounds of the table A aboveexcepted to compounds #72-#83.

A further object of the invention is a compound of formula (I) selectedin the group consisting of:

-   2-Benzamido-4-(4-chlorophenyl)thiophene-3-carboxylic acid (Compound    #1);-   2-Benzamido-4-(4-chloro-3-fluoro-phenyl)thiophene-3-carboxylic acid    (Compound #2);-   2-Benzamido-4-(4-chlorophenyl)-5-methyl-thiophene-3-carboxylic acid    (Compound #4);-   4-(4-Chlorophenyl)-2-[[4-(difluoromethoxy)benzoyl]amino]-5-methyl-thiophene-3-carboxylic    acid (Compound #5);-   2-Benzamido-5-chloro-4-(4-chloro-3-fluoro-phenyl)thiophene-3-carboxylic    acid (compound #6);-   2-Benzamido-4-norbornan-2-yl-thiophene-3-carboxylic acid (Compound    #9);-   2-Benzamido-4-cyclopentyl-thiophene-3-carboxylic acid (Compound    #10);-   4-Cyclohexyl-2-[[4-(difluoromethoxy)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #11);-   2-Benzamido-5-chloro-4-cyclohexyl-thiophene-3-carboxylic acid    (Compound #12);-   5-Chloro-4-cyclohexyl-2-[[4-(difluoromethoxy)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #13);-   5-Chloro-4-cyclohexyl-2-[(2-methylbenzoyl)amino]thiophene-3-carboxylic    acid (Compound #14);-   5-Chloro-4-cyclohexyl-2-[(4-morpholinobenzoyl)amino]thiophene-3-carboxylic    acid (Compound #15);-   2-Benzamido-5-chloro-4-cyclopentyl-thiophene-3-carboxylic acid    (Compound #18);-   2-Benzamido-4-[4-(trifluoromethyl)phenyl]thiophene-3-carboxylic acid    (Compound #20);-   2-Benzamido-4-(p-tolyl)thiophene-3-carboxylic acid (Compound #21);-   2-Benzamido-4-(3,4-dimethylphenyl)thiophene-3-carboxylic acid    (Compound #22);-   2-Benzamido-5-chloro-4-(3,4-dimethylphenyl)thiophene-3-carboxylic    acid (Compound #23);-   2-Benzamido-5-chloro-4-(p-tolyl)thiophene-3-carboxylic acid    (Compound #24);-   4-Cyclohexyl-2-[(3,4-dimethoxybenzoyl)amino]thiophene-3-carboxylic    acid (Compound #25);-   2-Benzamido-4-cyclohexyl-thiophene-3-carboxylic acid (Compound #26);-   2-Benzamido-4-cyclohexyl-5-methyl-thiophene-3-carboxylic acid    (Compound #27);-   2-[[4-(Difluoromethoxy)benzoyl]amino]-4-phenyl-thiophene-3-carboxylic    acid (Compound #28);-   4-Cyclohexyl-2-[(4-morpholinobenzoyl)amino]thiophene-3-carboxylicacid    (Compound #29);-   2-[[4-(Difluoromethoxy)benzoyl]amino]-5-methyl-4-phenyl-thiophene-3-carboxylic    acid (Compound #30);-   5-Chloro-2-[[4-(difluoromethoxy)benzoyl]amino]-4-phenyl-thiophene-3-carboxylic    acid (Compound #31);-   2-Benzamido-4-tert-butyl-thiophene-3-carboxylic acid (Compound #32);-   2-Benzamido-5-chloro-4-phenyl-thiophene-3-carboxylic acid (Compound    #33);-   2-Benzamido-5-methyl-4-phenyl-thiophene-3-carboxylic acid (Compound    #34);-   2-Benzamido-4-(3,3-difluorocyclobutyl)thiophene-3-carboxylic acid    (Compound #35);-   2-Benzamido-4-(3-chlorophenyl)thiophene-3-carboxylic acid (Compound    #36);-   2-Benzamido-4-norcaran-7-yl-thiophene-3-carboxylic acid (Compound    #37);-   2-Benzamido-4-(4-methoxyphenyl)thiophene-3-carboxylic acid (Compound    #38);-   2-Benzamido-4-(2,2,3,3-tetramethylcyclopropyl)thiophene-3-carboxylic    acid (Compound #39);-   2-Benzamido-4-methyl-5-phenyl-thiophene-3-carboxylic acid (Compound    #40);-   5-Cyclohexyl-2-[[4-(difluoromethoxy)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #41);-   2-[(2-Methylbenzoyl)amino]-4-phenyl-thiophene-3-carboxylic acid    (Compound #42);-   2-Benzamido-4-phenyl-thiophene-3-carboxylic acid (Compound #43);-   2-Benzamido-4-(2-chlorophenyl)thiophene-3-carboxylic acid (Compound    #44);-   2-[(2-Methylbenzoyl)amino]-5-phenyl-thiophene-3-carboxylic acid    (Compound #45);-   2-[(3,4-Dimethoxybenzoyl)amino]-4-phenyl-thiophene-3-carboxylic acid    (Compound #46);-   2-Benzamido-4-(trans-4-tert-butylcyclohexyl)thiophene-3-carboxylic    acid (Compound #48);-   2-Benzamido-5-chloro-4-[4-(trifluoromethyl)phenyl]thiophene-3-carboxylic    acid (Compound #50);-   2-Benzamido-4-(cis-4-tert-butylcyclohexyl)thiophene-3-carboxylic    acid (Compound #54);-   4-Cyclopentyl-2-[(4-morpholinobenzoyl)amino]thiophene-3-carboxylic    acid (Compound #59);-   4-Cyclopentyl-2-[[4-(tetrahydropyran-4-ylamino)benzoyl]    amino]thiophene-3-carboxylic acid (Compound #60);-   4-Cyclopentyl-2-[[4-(2-methoxyethylamino)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #61);-   4-Cyclopentyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #62);-   2-Benzamido-4-(3-phenylcyclobutyl)thiophene-3-carboxylic acid    (Compound #63);-   4-Cyclopentyl-2-[[4-(tetrahydropyran-4-ylmethylamino)    benzoyl]amino]thiophene-3-carboxylic acid (Compound #66);-   4-Cyclopentyl-2-[(3-morpholinobenzoyl)amino]thiophene-3-carboxylic    acid (Compound #71);-   2-Benzamido-4-chroman-3-yl-thiophene-3-carboxylic acid (Compound    #84);-   2-Benzamido-4-chroman-2-yl-thiophene-3-carboxylic acid (Compound    #85);-   2-Benzamido-4-cyclopropyl-thiophene-3-carboxylic acid (Compound    #87);-   4-Cyclopropyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #88);-   4-Cyclopropyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]    amino]thiophene-3-carboxylic acid (Compound #90);-   4-Tert-butyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]    thiophene-3-carboxylic acid (Compound #91);-   4-tert-Butyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #92);-   4-Chroman-3-yl-2-[[4-(2-methoxyethoxy)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #95);-   2-Benzamido-4-isobutyl-thiophene-3-carboxylic acid (Compound #96);-   4-Cyclobutyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #97);-   2-Benzamido-4-cyclobutyl-thiophene-3-carboxylic acid (Compound #98);-   4-Cyclobutyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]    amino]thiophene-3-carboxylic acid (Compound #99);-   2-[[4-(3-Methoxyazetidin-1-yl)benzoyl]amino]-4,5-dimethyl-thiophene-3-carboxylic    acid (Compound #100);-   4,5-Dimethyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]    thiophene-3-carboxylic acid (Compound #102);-   4-tert-Butyl-2-[[4-(2-methoxyethylamino)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #103);-   4-tert-Butyl-2-[[4-(3-ethoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #104);-   4-tert-Butyl-2-[[4-(tetrahydropyran-4-ylamino)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #105);-   4-(3,3-Difluorocyclobutyl)-2-[[4-(tetrahydropyran-4-ylmethylamino)    benzoyl]amino] thiophene-3-carboxylic acid (Compound #106);-   4-(3,3-Difluorocyclobutyl)-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #107);-   2-[[4-(2-Methoxyethylamino)benzoyl]amino]-4-(1-methylcyclopropyl)thiophene-3-carboxylic    acid (Compound #108);-   4-iso-Butyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid diethylamine salt (Compound #109);-   4-tert-Butyl-2-[[3-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #110);-   4-(1-Methylcyclopropyl)-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #111);-   2-[[4-(3-Methoxyazetidin-1-yl)benzoyl]amino]-4-(1-methylcyclopropyl)    thiophene-3-carboxylic acid (Compound #112);-   4-Isobutyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]    thiophene-3-carboxylic acid (Compound #113);-   5-Isopropyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]-4-methyl-thiophene-3-carboxylic    acid diethylamine salt (Compound #114);-   2-[[4-(3-Methoxyazetidin-1-yl)benzoyl]amino]-4-(1-methylcyclobutyl)    thiophene-3-carboxylic acid (Compound #115);-   4-tert-Butyl-2-[[4-(2-methoxyethoxy)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #116);-   4-tert-Butyl-2-[[4-[2-methoxyethyl(methyl)amino]benzoyl]    amino]thiophene-3-carboxylic acid (Compound #117);-   4-tert-Butyl-2-[[4-(tetrahydropyran-3-ylamino)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #118);-   4-tert-Butyl-2-[[4-(tetrahydropyran-3-ylmethylamino)benzoyl]amino]    thiophene-3-carboxylic acid (Compound #119);-   4-tert-Butyl-2-[[4-[methyl(tetrahydropyran-4-ylmethyl)amino]benzoyl]    amino]thiophene-3-carboxylic acid (Compound #120);-   4-tert-Butyl-2-[[2-fluoro-4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylic    acid (Compound #121); and-   2-Benzamido-4-(5,6,7,8-tetrahydroquinolin-2-yl)thiophene-3-carboxylic    acid (Compound #195).    Therapeutic Uses of Compounds

As illustrated by examples, the inventors have demonstrated thetherapeutic interest of the compounds of the invention.

Accordingly, the present invention relates to a pharmaceutical orveterinary composition comprising a new compound according to theinvention. Preferably, the pharmaceutical composition further comprisesa pharmaceutically or veterinary acceptable carrier or excipient. Thepresent invention relates to the use of a new compound according to theinvention as a drug or a medicine. The invention further relates to amethod for treating a disease in a subject, wherein a therapeuticallyeffective amount of a new compound according to the invention, isadministered to said subject in need thereof. The invention also relatesto the use of a new compound according to the invention, for themanufacture of a medicine. The invention also relates to apharmaceutical composition comprising a new compound according to theinvention for use as a drug.

The present invention relates to a new compound according to theinvention for use for treating a disease selected from the groupconsisting of an infection, preferably a viral or a bacterial infection,a cancer, a metabolic disease, a cardiovascular disease, an inflammatorydisorder, iron storage disease/disorder, aging and a neurodegenerativedisease or disorder. It further relates to the use of a new compoundaccording to the invention, for the manufacture of a medicine fortreating a disease selected from the group consisting of an infection,preferably a viral or a bacterial infection, a cancer, a metabolicdisease, a cardiovascular disease, an inflammatory disorder, ironstorage disease/disorder, aging and a neurodegenerative disease ordisorder. It also relates to a pharmaceutical composition comprising anew compound according to the invention for use for treating a diseaseselected from the group consisting of an infection, preferably a viralor a bacterial infection, a cancer, a metabolic disease, acardiovascular disease, an inflammatory disorder, iron storagedisease/disorder, aging and a neurodegenerative disease or disorder.Finally, it relates to a method for treating a disease selected from thegroup consisting of an infection, preferably a viral or a bacterialinfection, a cancer, a metabolic disease, a cardiovascular disease, aninflammatory disorder, iron storage disease/disorder, aging and aneurodegenerative disease or disorder in a subject in need thereof,wherein a therapeutically effective amount of a new compound accordingto the invention, is administered to said subject in need thereof.

In addition, the present invention relates to a method for treating aninfectious disease, preferably a viral disease, in a subject, wherein atherapeutically effective amount of a compound according to theinvention, is administered to said subject suffering of an infectiousdisease, preferably a viral disease. The present invention relates tothe use of the compounds according to the invention as ananti-infectious agent, preferably an antiviral agent. The invention alsorelates to the use of the compounds according to the invention, for themanufacture of a medicine for the treatment of an infectious disease,preferably a viral infection. The invention relates to a compoundaccording to the invention for use in the treatment of an infectiousdisease, preferably a viral infection.

The present invention further relates to a method for treating a cancerin a subject, wherein a therapeutically effective amount of a compoundaccording to the invention is administered to said subject suffering ofa cancer. The present invention relates to the use of the compoundsaccording to the invention as an antitumor agent. The invention alsorelates to the use of the compounds according to the invention, for themanufacture of a medicine for the treatment of a cancer. The inventionrelates to a compound according to the invention for use in thetreatment of a cancer.

The present invention further relates to a method for treating ametabolic disorder or disease in a subject, wherein a therapeuticallyeffective amount of a compound according to the invention isadministered to said subject suffering of a metabolic disorder ordisease. The invention also relates to the use of the compoundsaccording to the invention, for the manufacture of a medicine for thetreatment of a metabolic disorder or disease. The invention relates to acompound according to the invention for use in the treatment of ametabolic disorder or disease.

The present invention further relates to a method for treating acardiovascular disease in a subject, wherein a therapeutically effectiveamount of a compound according to the invention is administered to saidsubject suffering of a cardiovascular disease. The invention alsorelates to the use of the compounds according to the invention, for themanufacture of a medicine for the treatment of a cardiovascular disease.The invention relates to a compound according to the invention for usein the treatment of a cardiovascular disease.

The present invention further relates to a method for treating aninflammatory disease or disorder in a subject, wherein a therapeuticallyeffective amount of a compound according to the invention isadministered to said subject suffering of an inflammatory disease ordisorder. The invention also relates to the use of the compoundsaccording to the invention, for the manufacture of a medicine for thetreatment of an inflammatory disease or disorder. The invention relatesto a compound according to the invention for use in the treatment of aninflammatory disease or disorder.

The present invention also relates to a phytosanitary compositioncomprising a compound according to the invention. It also relates to theuse of a compound according to the invention, as a phytosanitary agent.Thereby, the compound according to the invention. It further relates toa method for treating a plant against infection, especially infection bya virus, comprising contacting the plant with an efficient amount of acompound according to the invention.

The present invention further relates to a method for treating aging ora neurodegenerative disease or disorder in a subject, wherein atherapeutically effective amount of a new compound according to theinvention is administered to said subject suffering of aging or aneurodegenerative disease or disorder. The invention also relates to theuse of a new compound according to the invention, for the manufacture ofa medicine for the treatment of aging or a neurodegenerative disease ordisorder. The invention relates to a new compound according to theinvention for use in the treatment of aging or a neurodegenerativedisease or disorder.

Antiviral Agents

The present invention relates to the use of a compound according to theinvention as an antiviral agent. The present invention also relates to acompound of the present invention for use in the treatment of viralinfections, the use of a compound of the present invention for themanufacture of a medicine for the treatment of viral infections, and toa method for treating a viral infection in a subject, comprisingadministering a therapeutically effective amount of a compound accordingto the invention to the subject.

The present invention also relates to the use of a compound of thepresent invention as a research tool, especially for studying viralinfections. It further relates to a method for blocking viral infectionin a cell, a tissue or a subject.

The viral agent can be a DNA virus or a RNA virus. The viral agent canbe selected from the group consisting of Alphaviridae, Flaviviridae,Hepadnaviridae, Herpesviridae, Orthomyxoviridae, Papovaviridae,Paramyxoviridae, Picornaviridae, Polyomaviridae, Reoviridae,Retroviridae, Rhabdoviridae, and Tobamoviruses.

In one embodiment, the Alphaviridae is selected from the groupconsisting of Barmah Forest virus, Middelburg virus, Ndumu virus, Bebaruvirus, Chikungunya virus, Mayaro virus, O'nyong'nyong virus, Ross Rivervirus, Semliki Forest virus, Sindbis virus, Una virus, Eastern equineencephalitis virus, Tonate virus, Venezuelan equine encephalitis virus,Cabassou virus, Everglades virus, Mosso das Pedras virus, Mucambo virus,Parmana virus, Pixuna virus, Rio Negro virus, Trocara virus, Aura virus,Babanki virus, Kyzylagach virus, Ockelbo virus, Whataroa virus, Sleepingdisease virus, Samon pancreatic disease virus, Southern elephant sealvirus, and Western equine encephalitis virus; preferably selected fromthe group consisting of Barmah Forest virus, Chikungunya virus, Mayarovirus, O'nyong'nyong virus, Ross River virus, Semliki Forest virus,Sindbis virus, Una virus, Eastern equine encephalitis virus, Tonatevirus, Venezuelan equine encephalitis virus and Western equineencephalitis virus.

In one embodiment, the Flaviviridae is selected from the groupconsisting of dengue virus, Hepatitis C virus, Japanese encephalitisvirus, West Nile virus, yellow fever virus, Zika virus, Tick-borneencephalitis virus, Kyasanur forest disease virus, Murray Valleyencephalitis virus, and Saint Louis encephalitis virus.

In one embodiment, the Hepadnaviridae is selected from the groupconsisting of Hepatitis B virus.

In one embodiment, the Herpesviridae is selected from the groupconsisting of Herpes Simplex virus 1 (HSV-1), Herpes Simplex virus 2(HSV-2), Varicella zoster virus (VZV), Epstein-Barr virus (EBV),Cytomegalovirus (CMV), Roseolovirus (HHV-6A and 6B), HHV-7 and Kaposi'ssarcoma-associated herpesvirus (KSHV).

In one embodiment, the Orthomyxoviridae is selected from the groupconsisting of Influenza virus A, Influenza virus B, Influenza virus C,Isavirus, Thogotovirus and Quaranjavirus, preferably selected from thegroup consisting of Influenza virus A and Influenza virus B. In oneembodiment, the Influenza virus A is selected from the subtypesconsisting of H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3,H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, and H10N7.

In one embodiment, the Papovaviridae is selected from the groupconsisting of Papillomavirus (HPC) and Polyomavirus, especially Simianvirus 40, Merkel cell polyomavirus, Trichodysplasia spinulosapolyomavirus, BK polyomavirus, JC polyomavirus and Human polyomavirus 7.

In one embodiment, the Paramyxoviridae is selected from the groupconsisting of Rubulavirus, Morbillivirus, Pneumovirus, Metapneumovirus,Avulavirus, Ferlavirus, Henipavirus, and Respirovirus. In a particularembodiment, the Paramyxoviridae is the mumps virus, measles virus, humanparainfluenza viruses (HPIV), especially HPIV-1, HPIV-2, HPIV-3 orHPIV-4, respiratory syncytial virus (RSV), in particular Humanrespiratory syncytial virus (HRSV), canine distemper virus, phocinedistemper virus, cetacean morbillivirus, Newcastle disease virus,rinderpest virus, Hendra birus virus an Nipah virus.

In one embodiment, the Picornaviridae is selected from the groupconsisting of Aphthovirus, Aquamavirus, Avihepatovirus, Cardiovirus,Cosavirus, Dicipivirus, Enterovirus, Erbovirus, Hepatovirus, Kobuvirus,Megrivirus, Parechovirus, Piscevirus, Rhinovirus, Salivirus,Sapelovirus, Senecavirus, Techovirus, and Tremovirus. In a particularembodiment, the Picornaviridae is a Rhinovirus, for instance aRhinovirus A, Rhinovirus B or Rhinovirus C.

In one embodiment, the Retroviridae is selected from the groupconsisting of Alpharetrovirus; especially Avian leukosis virus and Roussarcoma virus; Betaretrovirus, especially Mouse mammary tumour virus;Gammaretrovirus, especially Murine leukemia virus and Feline leukemiavirus; Deltaretrovirus, especially Bovine leukemia virus and HumanT-lymphotropic virus; Epsilonretrovirus, especially Walleye dermalsarcoma virus; Lentivirus, especially Human immunodeficiency virus 1 andSimian, Feline immunodeficiency viruses; Spumavirus, especially Simianfoamy virus.

In one embodiment, the Rhabdoviridae is selected from the groupconsisting of vesiculovirus, especially vesicular stomatitis virus,lyssavirus, rabies virus, Ephemerovirus, novirhabdovirus,cytorhabdovirus and nucleorhabdovirus.

In one preferred embodiment, the viral agent according to the inventionis selected from the group consisting in Herpesviridae such as Varicellazoster virus (VZV), Epstein-Barr (EB) virus, Herpes simplex virus oftype 1 (HSV-1), Kaposis sarcoma herpesvirus (KSHV), murine γ-HV68 virus(γ-MHV68), or human cytomegalovirus (HCMV); Hepadnaviridae such asHepatitis virus B (HBV); Papovaviridae such as Human papillomavirus type16 (HPV16); Parvoviridae such as Human parvovirus B19; Polyomaviridaesuch as Simian virus 40; Retroviridae such has Human immunodeficiencyvirus 1 (HIV-1), or Simian immunodeficiency virus type 1 (SIV 1);Orthomyxoviridae such as Influenza A virus; Flaviviridae such as Denguevirus, or Hepatitis C virus; Picornaviridae such as Poliovirus,Coxsakievirus B3 (CVB3), or Coxsakievirus B4 (CVB4); Reoviridae such asRotavirus; Alphaviridae such as Sindbis virus; Tobamoviruses such asTabacco mosaic virus; Rhabdoviridae such as vesicular stomatitis virus.More preferably, the viral agent according to the invention is aninfluenza virus. Still preferably, the viral agent according to theinvention is an influenza virus A or B, even more preferably aninfluenza virus A.

In another preferred embodiment, the viral agent according to theinvention presents an antiviral resistance to classic antiviral drugs.The terms “antiviral resistance”, “antiviral agent resistance” or“antiviral drug resistance”, as used herein, are equivalent and refer tothe ability of viruses to resist the effects of an antiviral agentpreviously used to treat them. Antiviral resistance can be defined by adecreased susceptibility to a drug through either a minimally effective,or completely ineffective, treatment response to prevent associatedillnesses from a particular virus.

In one embodiment, the compound of the invention can be used incombination with another antiviral drug, for instance andnon-exhaustively, an agent selected from the group consisting ofneuraminidase inhibitors, M2 inhibitors, RNA polymerase inhibitors,interferons (immune system modulators interferon alpha-2a and PEGylatedinterferon alpha-2a (Pegasys) and interferon alpha-2b (ViraferonPeg ouIntrona)), antiviral vaccine, antigenic polypeptides or neutralizingantibodies directed to a viral antigenic polypeptide.

Antibacterial Agents

The present invention relates to the use of a compound according to theinvention as an antibacterial agent. The present invention also relatesto a compound of the present invention for use in the treatment ofbacterial infections, the use of a compound of the present invention forthe manufacture of a medicine for the treatment of bacterial infections,and to a method for treating a bacterial infection in a subject,comprising administering a therapeutically effective amount of acompound according to the invention to the subject.

The bacterium can be gram-negative and gram-positive bacteria,preferably an infectious bacterium. Such gram-positive bacteria include,but are not limited to, Pasteurella species, Staphylococci species, andStreptococcus species.

Specific examples of bacteria include but are not limited to,Helicobacter pylori, Burkholderia cepacia, Pseudomonas aeruginosa,Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonasalcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Aeromonashydrophilia, Escherichia coli, Citrobacter freundii, Salmonellatyphimurium, Salmonella typhi, Salmonella paratyphi, Salmonellaenteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei,Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae,Klebsiella oxytoca, Serratia marcescens, Francisella tularensis,Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providenciaalcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacterbaumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus,Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis,Yersinia intermedia, Bordetella parapertussis, Bordetellabronchiseptica, Haemophilus parainfluenzae, Haemophilus haemolyticus,Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurellamultocida, Pasteurella haemolytica, Branhamella catarrhalis,Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borreliaburgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Listeriamonocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingelladenitrificans, Kingella indologenes, Kingella kingae, Kingella oralis,Legionella pneumophila, Moraxella bovis, Moraxella catarrhalis,Moraxella lacunata, Gardnerella vaginalis, Bacteroides fragilis,Bacteroides distasonis, Bacteroides vulgatus, Bacteroides ovalus,Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroideseggerthii, Bacteroides splanchnicus, Clostridium difficile, Clostridiumtetani, Mycobacterium species, Corynebacterium ulcerans, Streptococcusagalactiae, Gardnerella vaginitis, Streptococcus pyogenes, Enterococcusfaecalis, Enterococcus faecium, Fusobacterium nucleatum, Porphyromonasgingivalis, Vibrio vulnificus, Clostridium botulinum, Corynebacteriumdiptheriae, Staphylococcus aureus, Staphylococcus epidermidis,Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcushyicus, Staphylococcus haemolyticus, Staphylococcus hominis, orStaphylococcus saccharolyticus.

In a particular embodiment, the bacterium is a Mycobacterium, forinstance Mycobacterium species is selected from the group consisting ofM. africanum, M. bovis, M. bovis BCG, M. canetti, M. caprae, M. microti,M. mungi, M. orygis, M. pinnipedii, M. suricattae, M. tuberculosis, M.avium, M. avium paratuberculosis, M. avium silvaticum, M. avium“hominissuis”, M. colombiense, M. indicus pranii, M. asiaticum, M.gordonae, M. gastri and M. kansasii, M. hiberniae, M. nonchromogenicum,M. terrae, M. triviale, M. ulcerans, M. pseudoshottsii, M. shottsii, M.triplex, M. genavense, M. florentinum, M. lentiflavum, M. palustre, M.kubicae, M. parascrofulaceum, M. heidelbergense, M. interjectum, M.simiae, M. bohemicum, M. botniense, M. branderi, M. celatum, M.chimaera, M. conspicuum, M. cookie, M. doricum, M. farcinogenes, M.haemophilum, M. heckeshornense, M. intracellular, M. lacus, M. leprae,M. lepraemurium, M. lepromatosis, M. liflandii, M. malmoense, M.marinum, M. monacense, M. montefiorense, M. murale, M. nebraskense, M.saskatchewanense, M. scrofulaceum, M. shimoidei, M. szulgai, M. tusciae,M. xenopi, M. yongonense, M. intermedium, M. abscessus, M. chelonae, M.bolletii, M. fortuitum, M. fortuitum subsp. Acetamidolyticum, M.boenickei, M. peregrinum, M. porcinum, M. senegalense, M. septicum, M.neworleansense, M. houstonense, M. mucogenicum, M. mageritense, M.brisbanense, M. cosmeticum, M. parafortuitum, M. austroafricanum, M.diernhoferi, M. hodleri, M. hodleri, M. neoaurum, M. frederiksbergense,M. aurum, M. vaccae, M. chitae, M. fallax, M. confluentis, M.flavescens, M. madagascariense, M. phlei, M. smegmatis, M. goodie, M.wolinskyi, M. thermoresistibile, M. gadium, M. komossense, M. obuense,M. sphagni, M. agri, M. aichiense, M. alvei, M. arupense, M. brumae, M.canariasense, M. chubuense, M. conceptionense, M. duvalii, M.elephantis, M. gilvum, M. hassiacum, M. holsaticum, M. immunogenum, M.massiliense, M. moriokaense, M. psychrotolerans, M. pyrenivorans, M.vanbaalenii, M. pulveris, M. arosiense, M. aubagnense, M. caprae, M.chlorophenolicum, M. fluoroanthenivorans, M. kumamotonense, M.novocastrense, M. parmense, M. phocaicum, M. poriferae, M. rhodesiae, M.seoulense, and M. tokaiense, preferably Mycobacterium tuberculosis,Mycobacterium leprae, or Mycobacterium ulcerans.

In another preferred embodiment, the bacterium according to theinvention presents a resistance to classic antibacterial drugs. Theterms “antibacterial resistance”, “antibacterial agent resistance” or“antibacterial drug resistance”, as used herein, are equivalent andrefer to the ability of bacteria to resist the effects of anantibacterial agent previously used to treat them. Antibacterialresistance can be defined by a decreased susceptibility to a drugthrough either a minimally effective, or completely ineffective,treatment response to prevent associated illnesses from a particularbacterium.

In one embodiment, the compound of the invention can be used incombination with another antibacterial drug.

NEET Proteins Modulators

Compounds of the present invention are able to modulate NEET proteins.In particular, the compounds can be a NEET protein stabiliser.Alternatively, the compounds can be a NEET protein destabiliser.

The NEET protein family includes three class of proteins encoded by theCISD1, CISD2 and CISD3 genes.

CISD1 gene encodes the protein mitoNEET. It was previously calledC10orf70 or ZCD1 or MDS029. The gene encoding the protein is describedin databases GeneCards GCID GC10P058269; HGNC: 30880; Entrez Gene:55847; and UniGene: Hs.370102. The protein is described in UniProtKBunder: Q9NZ45. Amino acid and nucleotide reference sequences of mitoNEETare disclosed in GenPept and Genbank under NP_060934.1 and NM_018464.4,respectively.

CISD2 gene encodes the protein NAF-1 (nutrient-deprivation autophagyfactor-1). It was previously called WFS2 or ZCD2 and is also calledMiner1, ERIS (endoplasmic reticulum intermembrane small protein) andmitoNEET related 1. The gene encoding the protein is described indatabases GeneCards GCID GC04P102868; HGNC: 24212; Entrez Gene: 493856;and UniGene: Hs.444955. and Hs.745013. The protein is described inUniProtKB under: Q8N5K1. Amino acid and nucleotide reference sequencesof NAF-1 are disclosed in GenPept and Genbank under NP_001008389.1 andNM_001008388.4, respectively.

CISD3 gene encodes the protein Miner2. It is also calledmitoNEET-Related protein 2 or mitochondrial matrix-localizedmitochondrial inner NEET protein (MiNT). The gene encoding the proteinis described in databases GeneCards GCID GC17P038730; HGNC: 27578;Entrez Gene: 284106; and UniGene: Hs.713595. The protein is described inUniProtKB under ID P0C7P0. Amino acid and nucleotide reference sequencesof Miner2 are disclosed in GenPept and Genbank under NP 001129970.1 andNM 001136498.1, respectively. NEET proteins are important for humanhealth and disease. For instance, they are involved in oncology (Holt etal, 2016, J Cell Sci, 129, 155-165; Bai et al, 2015, Proc Natl Acad SciUSA, 112, 3698-3703; Tamir et al, 2014, Proc Natl Acad Sci USA, 111,5177-5182; Sohn et al, 2013, Proc Natl Acad Sci USA, 110, 14676-14681;Darash-Yahana et al, 2016, Proc Natl Acad Sci USA, 113, 10890-10895),especially apoptosis and autophagy; in metabolic disorders and diseases(Tamir et al, 2015, Biochim Biophys Acta, 1853, 1294-1315; Takahashi etal, Journal of Pharmacology and experimental therapeutics, 2015, 352,338-345); cardiovascular diseases (Du et al, 2015, Cell Biol Int, 39,816-823; Habener et al, 2016, PLoS One, 11, e0156054); inflammatorydiseases and disorders (Taminelli et al, 2008, Biochem Biophys ResCommun, 365, 856-862); iron storage disorders (REF); aging (Chen et al,2009, Genes Dev, 23, 1183-1194) and neurodegenerative diseases ordisorders (He et al, 2016, Sci Rep, 6, 35205). Studies demonstrated arole for mitoNEET and NAF-1 in the regulation of cellular iron, calciumand ROS homeostasis, and a key role for NEET proteins in criticalprocesses, such as cancer cell proliferation and tumor growth, lipid andglucose homeostasis in obesity and diabetes, control of autophagy,longevity in mice, and senescence in plants (Tamir et al, 2015, BiochimBiophys Acta, 1853, 1294-1315). Abnormal regulation of NEET proteins wasconsequently found to result in multiple health conditions. Forinstance, missplicing of NAF-1 causes Wolfram syndrome 2. NAF-1 is alsofunctionally linked to the regulation of autophagy in cancer and aging.

Cancers

The compounds of the present invention are able to kill tumor cells. Inaddition, the compounds of the present invention are also able tomodulate NEET proteins (Holt et al, 2016, J Cell Sci, 129, 155-165; Baiet al, 2015, Proc Natl Acad Sci USA, 112, 3698-3703; Tamir et al, 2014,Proc Natl Acad Sci USA, 111, 5177-5182; Sohn et al, 2013, Proc Natl AcadSci USA, 110, 14676-14681; Darash-Yahana et al, 2016, Proc Natl Acad SciUSA, 113, 10890-10895). NEET proteins are involved in the regulation ofapoptosis/autophagy in cancer biology. Accordingly, the presentinvention relates to the use of a compound of the present invention asan antitumor agent. The present invention also relates to a compound ofthe present invention for use for treating a cancer, the use of acompound of the present invention for the manufacture of a medicine fortreating a cancer, and to a method for treating a cancer in a subject,comprising administering an effective amount of a compound of thepresent invention to the subject.

In one aspect, the cancer can be a solid tumor or a hematopoieticcancer. For instance, the cancer can be selected from the groupconsisting of bone cancer, gastrointestinal cancer, liver cancer,pancreatic cancer, gastric cancer, colorectal cancer, esophageal cancer,oro-pharyngeal cancer, laryngeal cancer, salivary gland carcinoma,thyroid cancer, lung cancer, cancer of the head or neck, skin cancer,squamous cell cancer, melanoma, uterine cancer, cervical cancer,endometrial carcinoma, vulvar cancer, ovarian cancer, breast cancer,prostate cancer, cancer of the endocrine system, sarcoma of soft tissue,bladder cancer, kidney cancer, glioblastoma and various types of cancersof the central nervous system, lymphoma and leukemia. In a preferredembodiment, the cancer is a breast cancer, in particular atriple-negative breast cancer, prostate cancer and ovarian cancer. Inone particular embodiment, the cancer is a breast cancer.

Optionally, the compound of the present invention used for treatingcancer is a modulator of mitoNEET and/or NAF-1. In one aspect, thecompound is a modulator of mitoNEET. In another aspect, the compound isa modulator of NAF-1. In a further aspect, the compound is a modulatorof mitoNEET and NAF-1.

In this aspect, the compound of the present invention can be combinedwith radiotherapy, immunotherapy, hormonotherapy, or chemotherapy, allwell-known by the person skilled in the field.

Metabolic Disorders and Diseases

NEET proteins are involved in metabolic disorders and diseases (Tamir etal., 2015, Biochim Biophys Acta, 1853, 1294-1315). Accordingly, thepresent invention further relates to a method for treating a metabolicdisorder or disease in a subject, wherein a therapeutically effectiveamount of a compound according to the invention is administered to saidsubject suffering of a metabolic disorder or disease. The invention alsorelates to the use of the compounds according to the invention, for themanufacture of a medicine for the treatment of a metabolic disorder ordisease. The invention relates to a compound according to the inventionfor use in the treatment of a metabolic disorder or disease.

The metabolic disorders and diseases can be selected in the groupconsisting of diabetes mellitus, insulin resistance, insulin deficiency,hepatic steatosis, nonalcoholic fatty liver disease, Nonalcoholicsteatohepatitis (NASH), glucose intolerance, obesity, lipodystrophy,coronary heart disease, diabetic retinopathy, diabetic neuropathy,diabetic nephropathy, hypoglycemia, hyperglycemia, beta cell dysfunctionor hyperinsulinaemia, Wolfram syndrome, Polycystic ovary syndrome,pyruvate dehydrogenase deficiency, Albright hereditary osteodystrophy,cystinosis, fructose intolerance, Walker-Warburg syndrome,hypobetalipoproteinemia, Alström syndrome, and cirrhosis.

In one aspect, the metabolic disease or disorder can be selected fromthe group consisting of diabetes, in particular diabetes type I ordiabetes type II, atherosclerosis, obesity, diabetic neuropathies,lysosomal storage diseases, severe insulin resistance, hyperinsulinemia,hyperlipidemia, Rabson-Mendenhall syndrome, leprechaunism, lipoatrophicdiabetes, acute and chronic renal insufficiency, end-stage chronic renalfailure, glomerulonephritis, interstitial nephritis, pyelonephritis,glomerulosclerosis, and lipoatrophic diabetes, hepatic steatosis,nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis (NASH),glucose intolerance, lipodystrophy, coronary heart disease, diabeticretinopathy, diabetic neuropathy, diabetic nephropathy, hypoglycemia,hyperglycemia, beta cell dysfunction or hyperinsulinaemia, Wolframsyndrome, Polycystic ovary syndrome, pyruvate dehydrogenase deficiency,Albright hereditary osteodystrophy, cystinosis, fructose intolerance,Walker-Warburg syndrome, hypobetalipoproteinemia, Alström syndrome, andcirrhosis.

In another aspect, the metabolic disease or disorder can be selectedfrom the group consisting of activator deficiency/GM2 gangliosidosis,alpha-mannosidosis, aspartylglucoaminuria, cholesteryl ester storagedisease, chronic hexosaminidase A deficiency, cystinosis, Danon disease,Fabry disease, Farber disease, fucosidosis, galactosialidosis, GaucherDisease (Types I, II and III), GM1 Ganliosidosis, including infantile,late infantile/juvenile and adult/chronic), Hunter syndrome (MPS II),Mucolipidosis II, Infantile Free Sialic Acid Storage Disease (ISSD),Juvenile Hexosaminidase A Deficiency, Krabbe disease, Lysosomal acidlipase deficiency, Metachromatic Leukodystrophy, Hurler syndrome, Scheiesyndrome, Hurler-Scheie syndrome, Sanfilippo syndrome, Morquio Type Aand B, Maroteaux-Lamy, Sly syndrome, mucolipidosis, multiple sulfatedeficiency, Niemann-Pick disease, Neuronal ceroid lipofuscinoses, CLN6disease, Jansky-Bielschowsky disease, pycnodysostosis, Sandhoff disease,Schindler disease, and Tay-Sachs or Wolman disease.

In a preferred embodiment, metabolic disorders and diseases can beselected in the group consisting of diabetes mellitus, insulinresistance, obesity and Wolfram syndrome.

Optionally, the compound of the present invention used for treatingmetabolic diseases or disorders is a modulator of mitoNEET, NAF-1 and/orMiNT. In particular, it can be a modulator of a combination of NEETproteins, such as mitoNEET and NAF-1, mitoNEET and MiNT, NAF-1 and MiNTor mitoNEET, NAF-1 and MiNT. Alternatively, it can be a modulator ofmitoNEET, NAF-1 or MiNT.

The compound of the present invention can be combined with other drugsknown for their uses in the treatment of metabolic diseases ordisorders.

Cardiovascular Diseases

NEET proteins have been disclosed to be involved in cardiovasculardiseases and disorders (Du et al, 2015, Cell Biol Int, 39, 816-823;Habener et al, 2016, PLoS One, 11, e0156054; Tamir et al, 2015, BiochimBiophys Acta, 1853, 1294-1315). Therefore, the present invention furtherrelates to a method for treating a cardiovascular disease in a subject,wherein a therapeutically effective amount of a compound according tothe invention is administered to said subject suffering of acardiovascular disease. The invention also relates to the use of thecompounds according to the invention, for the manufacture of a medicinefor the treatment of a cardiovascular disease. The invention relates toa compound according to the invention for use in the treatment of acardiovascular disease.

In one aspect, the cardiovascular disease is selected from the groupconsisting of myocardial injury, Ischemia, Ischemia reperfusion injuryand hypertension. In one embodiment, the cardiovascular disease ismyocardial injury.

Optionally, the compound of the present invention used for treating acardiovascular disease is a modulator of mitoNEET and/or NAF-1. In oneaspect, the compound is a modulator of mitoNEET. In another aspect, thecompound is a modulator of NAF-1. In a further aspect, the compound is amodulator of mitoNEET and NAF-1.

The compound of the present invention can be combined with other drugsknown for their uses in the treatment of cardiovascular diseases ordisorders.

Inflammatory Diseases

NEET proteins have been disclosed to be involved in inflammation (Tamiret al, 2015, Biochim Biophys Acta, 1853, 1294-1315).

In one aspect, the inflammatory disease or disorder can be selected fromthe group consisting of Crohn disease, inflammatory bowel disease,asthma, chronic obtrusive pulmonary disease (COPD), systemic lupuserythematosus, cystic fibrosis, psoriasis, infectious arthritis, andmultiple sclerosis.

Optionally, the compound of the present invention used for treatinginflammatory diseases or disorders is a modulator of mitoNEET.

In one particular embodiment, the inflammatory disease or disorder iscystic fibrosis (Taminelli et al, 2008, Biochem Biophys Res Commun, 365,856-862). Optionally, the compound of the present invention used fortreating cystic fibrosis is a modulator of mitoNEET.

The compound of the present invention can be combined with other drugsknown for their uses in the treatment of inflammatory diseases ordisorders.

Iron Storage Disorders

NEET proteins are involved in iron homeostasis. The compounds of thepresent invention are able to modulate the NEET protein binding to iron,for instance by stabilizing and destabilizing this binding.

Accordingly, the present invention relates to a compound of the presentinvention for use for treating an iron storage disorder, the use of acompound of the present invention for the manufacture of a medicine fortreating an iron storage disorder, and to a method for treating an ironstorage disorder in a subject, comprising administering an effectiveamount of a compound of the present invention to the subject.

The iron storage disorder or disease can be associated to an irondeficiency or to an iron overload.

The iron storage disorders or diseases include, but are not limitedthereto, Ferroportin Deficiency, Hereditary Hemochromatosis, includingHereditary Hemochromatosis due to HFE mutations and HereditaryHemochromatosis due to transferrin receptor 2 mutations, JuvenileHemochromatosis, including Juvenile Hemochromatosis due to hepcidinmutations and Juvenile Hemochromatosis due to hemojuvelin mutations,Iron Overload, including African Iron Overload, Iron Overload secondaryto atransferrinemia and Iron Overload secondary to aceruloplasminemia,Thalassemia, Myelodysplastic Syndromes, Congenital DyserythropoieticAnemias, Sickle Cell Disease and other Hemoglobinopathies, Red CellEnzyme Deficiencies and Multiple Blood Transfusions.

Aging and Neurodegenerative Diseases

It is known that NEET proteins are involved in aging (Chen et al, 2009,Genes Dev, 23, 1183-1194) and in neurodegenerative diseases anddisorders (He et al, 2016, Sci Rep, 6, 35205). Therefore, a compound ofthe present invention, in particular a new compound of the presentinvention, can be used for the treatment of aging or a neurodegenerativedisease or disorder. Accordingly, the present invention relates to amethod for treating aging or a neurodegenerative disease or disorder ina subject, wherein a therapeutically effective amount of a compoundaccording to the invention, preferably a new one, is administered tosaid subject suffering of aging or a neurodegenerative disease ordisorder. The invention also relates to the use of a compound accordingto the invention, preferably a new one, for the manufacture of amedicine for the treatment of aging or a neurodegenerative disease ordisorder. The invention relates to a compound according to theinvention, preferably a new one, for use in the treatment of aging or aneurodegenerative disease or disorder.

In one embodiment, the compound of the present invention used fortreating aging or treating or preventing aging damage. Optionally, thecompound of the present invention used for treating aging is a modulatorof NAF-1.

In another embodiment, the compound of the present invention used fortreating a neurodegenerative disease or disorder. The neurodegenerativedisease can be selected from the group consisting of AdrenalLeukodystrophy, Alexander's disease, Alper's disease, Alzheimer'sdisease, Amyotrophic lateral sclerosis, ataxia telangiectasia, Battendisease, bovine spongiform encephalopathy, Canavan disease, cerebralpalsy, corticobasal degeneration, Creutzfeldt-Jakob disease, familialfatal insomnia, frontotemporal lobar degeneration, Huntington's disease,HIV-associated dementia, Kennedy's disease, Krabbe's disease, Lewy bodydementia, neuroborreliosis, Machado-Joseph disease, multiple systematrophy, multiple sclerosis, narcolepsy, Niemann Pick disease,Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease,primary lateral sclerosis, prion diseases, progressive supranuclearpalsy, Refsum's disease, Sandhoff disease, Schilder's disease, subacutecombined degeneration of spinal cord secondary to pernicious anaemia,Spielmeyer-Vogt-Sjogren-Batten disease, spinocerebellar ataxia, spinalmuscular atrophy, Steele-Richardson-Olszewski disease, Tabes dorsalisand toxic encephalopathy. Preferably, the neurodegenerative disease ordisorder can be selected from the group consisting of multiplesclerosis, Alzheimer's disease, Parkinson's disease and amyotrophiclateral sclerosis.

The neurodegenerative disease or disorder also includes central nervoussystem (CNS) injury.

Optionally, the compound of the present invention used for treating aneurodegenerative disease or disorder is a modulator of mitoNEET.

The compound of the present invention can be combined with other drugsknown for their uses in the treatment of neurodegenerative diseases ordisorders.

Pharmaceutical Composition

The present invention also relates to a pharmaceutical compositioncomprising a compound of the present invention, preferably a newcompound of the present invention. The composition further comprises atleast one pharmaceutically acceptable carrier or excipient.

In a particular embodiment, the pharmaceutical composition according tothe invention further comprises at least another active ingredient,preferably selected from the group consisting in an antiviral agent, ananti-cancerous agent, an antibiotic, or a molecule aimed to treatmetabolic diseases, cardiovascular diseases, inflammatory diseases,aging, muscle diseases, neurodegenerative diseases or iron storagedisorders. Preferably, the other active ingredient is an antiviralagent. More preferably, the other active ingredient is an antiviralagent against an influenza virus, preferably an influenza A virus.

In a particular embodiment, the pharmaceutical composition according tothe invention further comprises an antiviral agent, for instance andnon-exhaustively, an agent selected from the group consisting ofneuraminidase inhibitors, M2 inhibitors, RNA polymerase inhibitors,interferons (immune system modulators interferon alpha-2a and PEGylatedinterferon alpha-2a (Pegasys) and interferon alpha-2b (ViraferonPeg ouIntrona)), antiviral vaccine, antigenic polypeptides or neutralizingantibodies directed to a viral antigenic polypeptide.

The invention also concerns the pharmaceutical composition of theinvention for use in the treatment of a disease. The invention alsorelates to the use of a pharmaceutical composition according to theinvention for the manufacture of a medicine for treating a disease in asubject. The invention further relates to a method for treating adisease in a subject, wherein a therapeutically effective amount of apharmaceutical composition according to the invention is administered tosaid subject suffering from said disease.

The subject according to the invention is an animal, preferably amammal, even more preferably a human. However, the term “subject” canalso refer to non-human animals, in particular mammals such as dogs,cats, horses, cows, pigs, sheep, donkeys, rabbits, ferrets, gerbils,hamsters, chinchillas, rats, mice, guinea pigs and non-human primates,among others, that are in need of treatment.

The human subject according to the invention may be a human at theprenatal stage, a new-born, a child, an infant, an adolescent or anadult.

In a preferred embodiment, the subject has been diagnosed with adisease. Preferably, the subject has been diagnosed with a diseaseselected from the group consisting in viral infections, bacterialinfections, cancers, metabolic diseases or disorders, cardiovasculardiseases or disorders, inflammatory diseases or disorders, iron storagedisorders, aging and neurodegenerative diseases or disorders. Diagnosticmethods of these diseases are well known by the man skilled in the art.

The compound according to the invention or the pharmaceuticalcomposition according to the invention may be administered by anyconventional route of administration. In particular, the compound or thepharmaceutical composition of the invention can be administered by atopical, enteral, oral, parenteral, intranasal, intravenous,intra-arterial, intramuscular, intratumoral, subcutaneous or intraocularadministration and the like.

In particular, the compound according to the invention or thepharmaceutical composition according to the invention can be formulatedfor a topical, enteral, oral, parenteral, intranasal, intravenous,intra-arterial, intramuscular, intratumoral, subcutaneous or intraocularadministration and the like.

Preferably, the compound according to the invention or thepharmaceutical composition according to the invention is administered byenteral or parenteral route of administration. When administeredparenterally, the compound according to the invention or thepharmaceutical composition according to the invention is preferablyadministered by intravenous route of administration. When administeredenterally, the compound according to the invention or the pharmaceuticalcomposition according to the invention is preferably administered byoral route of administration.

The pharmaceutical composition comprising the molecule is formulated inaccordance with standard pharmaceutical practice (Lippincott Williams &Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J.Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York) known bya person skilled in the art.

For oral administration, the composition can be formulated intoconventional oral dosage forms such as tablets, capsules, powders,granules and liquid preparations such as syrups, elixirs, andconcentrated drops. Nontoxic solid carriers or diluents may be usedwhich include, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharine, talcum, cellulose,glucose, sucrose, magnesium, carbonate, and the like. For compressedtablets, binders, which are agents which impart cohesive qualities topowdered materials, are also necessary. For example, starch, gelatine,sugars such as lactose or dextrose, and natural or synthetic gums can beused as binders. Disintegrants are also necessary in the tablets tofacilitate break-up of the tablet. Disintegrants include starches,clays, celluloses, algins, gums and crosslinked polymers. Moreover,lubricants and glidants are also included in the tablets to preventadhesion to the tablet material to surfaces in the manufacturing processand to improve the flow characteristics of the powder material duringmanufacture. Colloidal silicon dioxide is most commonly used as aglidant and compounds such as talc or stearic acids are most commonlyused as lubricants.

For transdermal administration, the composition can be formulated intoointment, cream or gel form and appropriate penetrants or detergentscould be used to facilitate permeation, such as dimethyl sulfoxide,dimethyl acetamide and dimethylformamide.

For transmucosal administration, nasal sprays, rectal or vaginalsuppositories can be used. The active compound can be incorporated intoany of the known suppository bases by methods known in the art. Examplesof such bases include cocoa butter, polyethylene glycols (carbowaxes),polyethylene sorbitan monostearate, and mixtures of these with othercompatible materials to modify the melting point or dissolution rate.

Pharmaceutical compositions according to the invention may be formulatedto release the active drug substantially immediately upon administrationor at any predetermined time or time period after administration.

Preferably, the treatment with the compound according to the inventionor the pharmaceutical composition according to the invention start nolonger than a month, preferably no longer than a week, after thediagnosis of the disease. In a most preferred embodiment, the treatmentstarts the day of the diagnosis.

The compound according to the invention or the pharmaceuticalcomposition according to the invention may be administered as a singledose or in multiple doses.

Preferably, the treatment is administered regularly, preferably betweenevery day and every month, more preferably between every day and everytwo weeks, more preferably between every day and every week, even morepreferably the treatment is administered every day. In a particularembodiment, the treatment is administered several times a day,preferably 2 or 3 times a day, even more preferably 3 times a day.

The duration of treatment with the compound according to the inventionor the pharmaceutical composition according to the invention ispreferably comprised between 1 day and 20 weeks, more preferably between1 day and 10 weeks, still more preferably between 1 day and 4 weeks,even more preferably between 1 day and 2 weeks. In a particularembodiment, the duration of the treatment is of about 1 week.Alternatively, the treatment may last as long as the disease persists.

The amount of compound according to the invention or of pharmaceuticalcomposition according to the invention to be administered has to bedetermined by standard procedure well known by those of ordinary skillsin the art. Physiological data of the patient (e.g. age, size, andweight) and the routes of administration have to be taken into accountto determine the appropriate dosage, so as a therapeutically effectiveamount will be administered to the patient.

In a preferred embodiment, the total compound dose for eachadministration of the compound according to the invention or of thepharmaceutical composition according to the invention is comprisedbetween 0.00001 and 1 g, preferably between 0.01 and 10 mg.

The form of the pharmaceutical compositions, the route of administrationand the dose of administration of the compound according to theinvention, or the pharmaceutical composition according to the inventioncan be adjusted by the man skilled in the art according to the type andseverity of the disease, and to the patient, in particular its age,weight, sex, and general physical condition.

Kit and Use of a Kit

The present invention also relates to the combined use of a compound ofthe present invention with at least another active ingredient,preferably selected from the group consisting in an antiviral agent, ananti-cancerous agent, an anti-apoptotic agent, an anti-autophagy agent,an autophagy inducing agent, an antibiotic, an antiparasitic agent, anantifungal agent, or a molecule aimed to treat neurodegenerativediseases, inflammatory diseases, autoimmune diseases, liver diseases,aging, muscle diseases, or metabolic diseases for the treatment of adisease selected from the group consisting of cancer, infectiousdiseases, in particular viral diseases, metabolic diseases or disorders,cardiovascular diseases or disorders, inflammatory diseases, ironstorage disorders, aging, and neurodegenerative diseases.

The present invention also relates to a product comprising a compound ofthe present invention, and another active ingredient, as a combinedpreparation for simultaneous, separate or sequential use, in particularfor use for the treatment of a disease selected from the groupconsisting of cancer, infectious diseases, in particular viral diseases,metabolic diseases or disorders, cardiovascular diseases or disorders,inflammatory diseases, iron storage disorders, aging, andneurodegenerative diseases. Preferably, the other active ingredient isselected from the group consisting in an antiviral agent, ananti-cancerous agent, an anti-apoptotic agent, an anti-autophagy agent,an autophagy inducing agent, an antibiotic, an antiparasitic agent, anantifungal agent, or a molecule aimed to treat cancer, infectiousdiseases, in particular viral diseases, metabolic diseases or disorders,cardiovascular diseases or disorders, inflammatory diseases, ironstorage disorders, aging, and neurodegenerative diseases. Preferably,the other active ingredient is an antiviral.

Further aspects and advantages of the present invention will bedescribed in the following examples, which should be regarded asillustrative and not limiting.

EXAMPLES Example A—Chemistry Abbreviations

-   -   Aq Aqueous    -   br s Broad singlet    -   CDCl₃ Deuteratedchloroform    -   d Doublet    -   DAD Diode Array Detector    -   DCM Dichloromethane (methylene chloride)    -   dd Doublet of doublets    -   ddd Doublet of doublets of doublets    -   DMF N,N-Dimethylformamide    -   DMSO Dimethyl sulfoxide    -   dt Doublet of triplets    -   EtOAc Ethyl acetate    -   Et₂O Diethyl ether    -   EtOH Ethanol    -   g Gram(s)    -   h Hour(s)    -   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   HCl Hydrochloric acid    -   HPLC High-pressure liquid chromatography    -   i-PrOH Isopropanol    -   LC/MS Liquid chromatography/mass spectrometry    -   LiOH Lithium hydroxide    -   m Multiplet    -   M Molar    -   MeCN Acetonitrile    -   MeOH Methyl alcohol    -   MgSO₄ Magnesium sulfate    -   min Minute(s)    -   mmol Millimole    -   MHz MegaHertz    -   MS Mass spectrometry    -   N Normal    -   NaHCO₃ Sodium bicarbonate    -   NH₄Cl Ammonium chloride    -   NMR Nuclear magnetic resonance    -   p para    -   PDA Photodiode Array    -   pH −log[H⁺]    -   ppm Parts per million    -   q Quadruplet    -   quin Quintuplet    -   RP-HPLC Reverse-phase high-pressure liquid chromatography    -   Rt Retention time    -   RT Room temperature    -   s Singlet    -   t Triplet    -   td Triplet of doublets    -   TFA Trifluoroacetic acid    -   tert-Tertiary    -   THF Tetrahydrofuran

General Synthetic Schemes

Compounds of the invention may be prepared using the synthetictransformations illustrated in Schemes I-V. Starting materials arecommercially available or may be prepared by the procedures describedherein, by literature procedures, or by procedures that would be wellknown to one skilled in the art of organic chemistry. Unless stated, allaqueous solutions are saturated.

Methods for preparing 2-benzamidothiophene-3-carboxylic acid compounds 5of the invention containing various substitutions on position 4 and 5 ofthe thiophene and on the benzamides are illustrated in Scheme I. InScheme I, step a, the 2-aminothiophene-3-carboxylate scaffold 3 can becommercially available or synthesised from commercially availablecyanoacetate 2 and acyclic ketones 1 in a 3-component reaction usingsulfur and a suitable base. This reaction, called Gewald reaction (asdescribed in Ber., 1966, 99, 94-100), can be carried out using forexample one of the procedures described in Example #2, or by methodsknown to one skilled in the art (for example, Eur. J. Med. Chem., 2016,123, 31-47) to provide the 2-aminothiophene-3-carboxylate basedcompounds 3. 2-Aminothiophenes 3 may react with substituted benzoylchloride as described in Scheme I, step b using conditions such as thosedescribed in Example #1, or by methods known to one skilled in the art(for instance, J. Med. Chem., 2013, 56(24), 10118-10131) to give2-(benzamido)thiophene-3-carboxylate derivatives 4. Acyl chlorides canbe commercially available or synthesised as described in Example #83 orby methods known to one skilled in the art (for example, J. Med. Chem.,2016, 59(13), 6201-6220). In Scheme I, step c, the ester of2-(benzamido)thiophene-3-carboxylate derivatives 4 may be hydrolysed tothe 2-(benzamido)thiophene-3-carboxylic acids 5 using conditions such asthose described in Example #1 or by methods known to one skilled in theart (for example, J. Med. Chem., 2013, 56(24), 10118-10131).

Methods for preparing acyclic ketones 1 used in Scheme 1, step a, areillustrated in Scheme II. In Scheme II, step d, the Weinreb amide 7 maybe synthesised from commercially available carboxylic acid 6 using forexample one of the procedures described in Example #31, or by methodsknown to one skilled in the art (for example, Organic Letters, 2012, 14,5518-5521). Acyclic ketones 1 may be synthesized from Weinreb amide 7using conditions such as those described in Example #31, or by methodsknown to one skilled in the art (for example, Synthesis, 2018, 50,4949-4957).

Methods for preparing 2-benzamido-5-chloro-thiophene-3-carboxylic acidcompounds 10 of the invention containing various substitutions onposition 4 of the thiophene and on the benzamides are illustrated inScheme III and IV. In Scheme III, step f, the2-amino-5-chloro-thiophene-3-carboxylate compounds 8 may be synthesisedfrom 2-aminothiophene-3-carboxylate derivatives 3 of commercialavailability, or prepared via the Gewald cyclisation described in SchemeI, step a, using for example the procedure described in Example #5, orby methods known to one skilled in the art (for example, Journal ofHeterocyclic Chemistry, 2008, 45, 201-207). 2-Aminothiophenes 8 mayreact with substituted benzoyl chloride as described in Scheme III, stepg using conditions such as those described in Example #1, or by methodsknown to one skilled in the art (for instance, J. Med. Chem., 2013,56(24), 10118-10131) to give2-(benzamido)-5-chloro-thiophene-3-carboxylate derivatives 9. In SchemeIII, step h, the ester of 2-(benzamido)-5-chloro-thiophene-3-carboxylatederivatives 9 may be hydrolysed to the2-(benzamido)-5-chloro-thiophene-3-carboxylic acids 10 using conditionssuch as those described in Example #1 or Example #12, or by methodsknown to one skilled in the art (for example, J. Med. Chem., 2013,56(24), 10118-10131).

Alternative methods for preparing2-benzamido-5-chloro-thiophene-3-carboxylic acid compounds 10 of theinvention containing various substitutions on position 4 of thethiophene and on the benzamides are illustrated in Scheme IV. In SchemeIV, step i, the 2-(benzamido)-5-chloro-thiophene-3-carboxylate compounds9 may be synthesised from 2-(benzamido)thiophene-3-carboxylatederivatives 4, prepared as described in Scheme I, step b (R¹ ═H), usingconditions such as those described in Preparation #1, step C.

Compounds of general structure 4 may be modified later in the synthesisas described in Scheme V. 2-Aminothiophenes 3 may react with halobenzoylchloride as described in Scheme V, step b using, for example, similarconditions described in Scheme I, step b. In Scheme V, step k, the4-halobenzamide 13 may be reacted with an amine as described inPreparation #1, Step B, for example, or by methods known to one skilledin the art (for example, J. Med. Chem., 2016, 59, 3489-3498). In SchemeV, step c, the ester of 2-(4-aminobenzamido)thiophene-3-carboxylatederivatives 14 may be hydrolysed to the2-(4-aminobenzamido)thiophene-3-carboxylic acids 15 using conditionssuch as those described in Scheme I, step c.

Analytical Methods

All ¹H NMR data were collected on a Bruker Avance 400 MHz equipped with5 mm QNP probe or Bruker Avance III 400 MHz, 5 mm BBFO Plus probeinstruments and chemical shifts are quoted in parts per million (ppm).LC/MS data is referenced to LC/MS conditions using the method numberprovided in Table 1.

TABLE 1 LC/MS analysis methods Method Conditions A LC/MS analysiscondition: Column: Acquity UPLC BEH Shield RP18 1.7 μm, 100 × 2.1 mmplus guard cartridge, maintained at 40° C. Mobile phase: MeCN in water(with 10 mM ammonium bicarbonate), from 5% to 95% within 6 min; Flowrate: 0.5 ml/min; Wavelength: 210-400 nm DAD. Waters DAD + Waters SQD2,single quadrapole UPLC-MS B LC/MS analysis condition: Column: AcquityUPLC HSS C18 1.8 μm, 100 × 2.1 mm plus guard cartridge, maintained at40° C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formicacid), from 5% to 95% within 6 min; Flow rate: 0.5 ml/min; Wavelength:210-400 nm DAD. Waters DAD + Waters SQD2, single quadrapole UPLC-MS CLC/MS analysis condition: Column: ACQUITY UPLC BEH C₁₈ 1.7 μm, 100 × 2.1mm, maintained at 40° C. Mobile phase: MeCN (0.1% formic acid) in water(0.1% formic acid), from 5% to 95% within 8 min; Flow rate: 0.4 ml/min;Wavelength: 200-500 nm DAD. Acquity i-Class (quarternary pump/PDAdetector) + Quattro Micro Mass Spectrometer D LC/MS analysis condition:Column: Acquity UPLC HSS C18 1.8 μm, 100 × 2.1 mm plus guard cartridge,maintained at temp. Mobile phase: MeCN (0.1% formic acid) in water (0.1%formic acid), from 5% to 95% within 8 min; Flow rate: 0.4 ml/min;Wavelength: 210-400 nm DAD. Waters DAD + Waters SQD2, single quadrapoleUPLC-MS E LC/MS analysis condition: Column: Acquity UPLC BEH Shield RP181.7 μm, 100 × 2.1 mm plus guard cartridge, maintained at temp. Mobilephase: MeCN in water (with 10 mM ammonium bicarbonate), from 5% to 95%within 8 min; Flow rate: 0.4 ml/min; Wavelength: 210-400 nm DAD. WatersDAD + Waters SQD2, single quadrapole UPLC-MS

For the general procedures, intermediate and final compounds may bepurified by any technique or combination of techniques known to oneskilled in the art. Some examples that are not limiting include flashchromatography with a solid phase (i.e. silica gel, alumina, etc.) and asolvent (or combination of solvents, i.e. heptane, EtOAc, DCM, MeOH,MeCN, water, etc.) that elutes the desired compounds; RP-HPLCpurification performed on Agilent Technologies 1260 Infinitypurification system and Agilent 6120 series Single Quadrupole MassSpectrometer (see Table 2 for some non-limiting conditions);recrystallization from an appropriate solvent (i.e. MeOH, EtOH, i-PrOH,EtOAc, toluene, etc.) or combination of solvents (i.e. EtOAc/heptane,EtOAc/MeOH, etc.); precipitation from a combination of solvents (i.e.DMF/water, DMSO/DCM, EtOAc/heptane, etc.); trituration with anappropriate solvent (i.e. EtOAc, DCM, MeCN, MeOH, EtOH, i-PrOH, n-PrOH,etc.); extractions by dissolving a compound in a liquid and washing withan appropriately immiscible liquid (i.e. DCM/water, EtOAc/water,DCM/saturated NaHCO₃, EtOAc/saturated NaHCO₃, DCM/10% aqueous HCl,EtOAc/10% aqueous HCl, etc.); distillation (i.e. simple, fractional,Kugelrohr, etc.). Descriptions of these techniques can be found in thefollowing references: Gordon, A. J. and Ford, R. A. “The Chemist'sCompanion”, 1972; Palleros, D. R. “Experimental Organic Chemistry”,2000; Still, W. C., Kahn and M. Mitra, A. J. Org. Chem. 1978, 43(14),2923-2925; Yan, B. “Analysis and Purification Methods in CombinatorialChemistry” 2003; Harwood, L. M., Moody, C. J. and Percy, J. M.“Experimental Organic Chemistry: Standard and Microscale, 2^(nd)Edition”, 1999.

TABLE 2 RP-HPLC purification methods Method Conditions A RP-HPLCpurification condition: Column Waters Xbridge Phenyl 10 μm, 100 × 19 mm.Mobile phase: MeOH in water (0.1% ammonium bicarbonate); Flow rate: 20ml/min; Wavelength: 210-400 nm DAD. Sample injected in DMSO, 23 minnon-linear gradient from 5% to 100% MeOH, centered on a specific focusedgradient

PREPARATIONS AND EXAMPLES

All starting materials are commercially available from Sigma-Aldrich(including Fluka and Discovery CPR) or Acros unless otherwise notedafter the chemical name. Reagent/reactant names given are as named onthe commercial bottle or as generated by IUPAC conventions or ChemDraw16.0. None of the specific conditions and reagents noted herein is to beconstrued as limiting the scope of the invention and are provided forillustrative purposes only.

Example #1. 2-Benzamido-4-(4-chlorophenyl)thiophene-3-carboxylic acid(Compound #1)

To a solution of ethyl 2-amino-4-(4-chlorophenyl)-3-thiophenecarboxylate(CAS: 65234-09-5, 150 mg, 0.53 mmol) in DCM (7.0 ml) was added DIPEA(CAS: 7087-68-5, 190 μl, 1.12 mmol) and benzoyl chloride (CAS: 98-88-4,83 μl, 0.72 mmol). The reaction mixture was stirred at room temperatureovernight. The resulting mixture was diluted with DCM and a saturatedaqueous NaHCO₃ solution and the two phases were separated. The organicphase was washed with a 1N aqueous HCl solution, dried over MgSO₄ andthe solvent was removed under reduced pressure to afford ethyl2-benzamido-4-(4-chlorophenyl)thiophene-3-carboxylate as an off-whitesolid (205 mg, yield quant.). Ethyl2-benzamido-4-(4-chlorophenyl)thiophene-3-carboxylate (205 mg, 0.53mmol) was dissolved in THF (5.0 ml), MeOH (5.0 ml) and water (5.0 ml).To the solution was added lithium hydroxide monohydrate (CAS:11310-65-2, 145 mg, 3.45 mmol). The reaction mixture was stirred at 65°C. for 1 hour. The mixture was cooled to RT and the volatiles wereremoved under reduced pressure. The residue was acidified with a 1Naqueous HCl solution and the aqueous phase was then extracted withEtOAc, the organic phase was dried over MgSO₄ and the solvent wasremoved under reduced pressure. Purification by flash chromatography onsilica gel (eluting with 0-100% DCM in isohexane, followed by 0-5% MeOHin DCM), followed by trituration with DCM/isohexane afforded2-benzamido-4-(4-chlorophenyl)thiophene-3-carboxylic acid as anoff-white solid (30 mg, yield 16%). ¹H NMR (DMSO-d₆, 400 MHz): δ=13.26(s, 1H), 12.52 (s, 1H), 8.00-7.95 (m, 2H), 7.73 (tt, J=1.7, 7.3 Hz, 1H),7.69-7.63 (m, 2H), 7.45-7.37 (m, 4H), 7.01 ppm (s, 1H). LC/MS (Table 1,Method B) R_(t)=3.66 min; MS n/z: 358 [M+H]⁺.

Example #2.2-Benzamido-4-(4-chloro-3-fluoro-phenyl)thiophene-3-carboxylic acid(Compound #2)

To a solution of 1-(4-chloro-3-fluorophenyl)ethan-1-one (CAS:151945-84-5, 1.00 g, 5.79 mmol) in ethanol (15 ml) was added ethylcyanoacetate (CAS: 105-56-6, 0.62 ml, 5.79 mmol), sulfur (CAS:7704-34-9, 186 mg, 5.79 mmol) and morpholine (CAS: 110-91-8, 1.5 ml,17.38 mmol). The reaction mixture was heated at 80° C. for 48 hours andthen cooled at RT. The volatiles were removed under reduced pressure andthe residue was partitioned between EtOAc and brine and the two phaseswere separated. The organic phase was washed with brine, dried overMgSO₄ and the solvent was removed under reduced pressure. Purificationby flash chromatography on silica gel (eluting with 0-40% EtOAc inisohexane) afforded ethyl2-amino-4-(4-chloro-3-fluorophenyl)thiophene-3-carboxylate as on oil(589 mg, yield 34%). To a solution of ethyl2-amino-4-(4-chloro-3-fluorophenyl)thiophene-3-carboxylate (300 mg, 1.00mmol) in DCM (7.0 ml) was added DIPEA (CAS: 7087-68-5, 520 μl, 3.00mmol) and benzoyl chloride (CAS: 98-88-4, 140 μl, 1.20 mmol). Thereaction mixture was stirred at RT overnight. The resulting mixture wasdiluted with DCM and the organic phase was washed with a 1N aqueous HClsolution and brine. The organic phase was dried over MgSO₄ and thesolvent was removed under reduced pressure. Purification by flashchromatography on silica gel (eluting with 0-25% EtOAc in isohexane)afforded ethyl2-benzamido-4-(4-chloro-3-fluorophenyl)thiophene-3-carboxylate as awhite solid (199 mg, 0.493 mmol), which was dissolved in THF (4.0 ml),MeOH (4.0 ml) and water (4.0 ml). To the solution was added lithiumhydroxide monohydrate (CAS: 1310-66-3, 103 mg, 2.46 mmol) and thereaction mixture was stirred at RT overnight and at 40° C. for 2 hours.The mixture was cooled to RT and diluted with EtOAc and a 1N aqueous HClsolution. The two phases were separated and the organic phase was washedwith brine, dried over MgSO₄ and the solvent was removed under reducedpressure. Purification by RP-HPLC (Table 2, Method A) afforded2-benzamido-4-(4-chloro-3-fluoro-phenyl)thiophene-3-carboxylic acid asan off-white solid (72.8 mg, yield 19%). ¹H NMR (DMSO-d₆, 400 MHz):δ=13.86 (br s, 1H), 8.02 (d, J=7.1 Hz, 2H), 7.76-7.63 (m, 3H), 7.58 (t,J=8.1 Hz, 1H), 7.48 (dd, J=1.7, 10.7 Hz, 1H), 7.28 (dd, J=1.4, 8.2 Hz,1H), 7.20 (br s, 1H), 7.02 ppm (s, 1H). LC/MS (Table 1, Method A)R_(t)=2.84 min; MS m/z: 376 [M+H]⁺.

Example #3.2-Benzamido-4-(4-chlorophenyl)-5-methyl-thiophene-3-carboxylic acid(Compound #4)

The title compound was synthesized according to the procedure describedin Example #1 using ethyl2-amino-4-(4-chlorophenyl)-5-methylthiophene-3-carboxylate (CAS:350989-77-4) as a starting material (yellow solid, yield 55%). ¹H NMR(DMSO-d₆, 400 MHz): δ=13.10 (s, 1H), 12.55 (s, 1H), 7.99 (d, J=7.6 Hz,2H), 7.78-7.63 (m, 3H), 7.48 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H),2.18 ppm (s, 3H). LC/MS (Table 1, Method A) R_(t)=2.81 min; MS m/z: 372[M+H]⁺.

Example #4.4-(4-Chlorophenyl)-2-[[4-(difluoromethoxy)benzoyl]amino]-5-methyl-thiophene-3-carboxylicacid (Compound #5)

The title compound was synthesized according to the procedure describedin Example #1 using ethyl2-amino-4-(4-chlorophenyl)-5-methylthiophene-3-carboxylate (CAS:350989-77-4) and 4-(difluoromethoxy)benzoyl chloride (CAS: 57320-63-5)as starting materials (off-white solid, yield 56%). ¹H NMR (DMSO-ds, 400MHz): δ=14.30 (s, 1H), 8.05 (d, J=8.9 Hz, 2H), 7.64-7.25 (m, 8H), 2.17ppm (s, 3H). LC/MS (Table 1, Method A) R_(t)=2.91 min; MS I/z: 438[M+H]⁺.

Example #5.2-Benzamido-5-chloro-4-(4-chloro-3-fluoro-phenyl)thiophene-3-carboxylicacid (compound #6)

To a solution of ethyl2-amino-4-(4-chloro-3-fluorophenyl)thiophene-3-carboxylate (synthesizedaccording to the procedure described in Example #2, 250 mg, 0.83 mmol)in chloroform (5.0 ml) at −5° C. was added N-chlorosuccinimide (CAS:128-09-6). The reaction mixture was stirred at −5° C. for 1 hour, thendiluted with DCM and poured into an aqueous sodium thiosulfate solution(5%). The two phases were separated, the organic phase was washed withbrine, dried over MgSO₄ and the solvent was removed under reducedpressure. Purification by flash chromatography on silica gel (elutingwith 0-20% EtOAc in isohexane) afforded ethyl2-amino-5-chloro-4-(4-chloro-3-fluorophenyl)thiophene-3-carboxylate asan oil (170 mg, yield 61%). The title compound was then synthesizedaccording to the procedure described in Example #1 using ethyl2-amino-5-chloro-4-(4-chloro-3-fluorophenyl)thiophene-3-carboxylate andbenzoyl chloride (CAS: 98-88-4) as starting materials (white solid,yield 14%). ¹H NMR (DMSO-d₆, 400 MHz): δ=13.35 (s, 1H), 12.58 (s, 1H),7.84-7.78 (m, 2H), 7.62-7.46 (m, 4H), 7.29 (dd, J=1.9, 10.3 Hz, 1H),7.04 ppm (dd, J=1.4, 8.3 Hz, 1H). LC/MS (Table 1, Method A) R_(t)=3.03min; MS m/z: 410 [M+H]⁺.

Example #6. 2-Benzamido-4-norbornan-2-yl-thiophene-3-carboxylic acid(Compound #9)

The title compound, isolated as mixture of isomers (ratio 85:15), wassynthesized according to the procedure described in Example #2 using1-bicyclo[2.2.1]hept-2-ylethanone (CAS: 58654-66-3) as a startingmaterial (white solid, yield 13%). ¹H NMR (DMSO-d₆, 400 MHz): δ=13.50(s, 1H), 12.64 (s, 1H), 7.96-7.92 (m, 2H), 7.73-7.61 (m, 3H), 6.88 (s,0.15H, minor isomer), 6.71 (s, 0.85H, major isomer), 3.79-3.75 (m 0.15H,minor isomer), 3.30-3.24 (m 0.85H, major isomer, partially obscured bythe water peak), 2.29-2.25 (m, 2H), 1.71-1.08 ppm (m, 8H). LC/MS (Table1, Method B) Rt=3.86 min; MS m/z: 342 [M+H]⁺.

Example #7. 2-Benzamido-4-cyclopentyl-thiophene-3-carboxylic acid(Compound #10)

The title compound was synthesized according to the procedure describedin Example #2 using 1-cyclopentylethanone (CAS: 6004-60-0) as a startingmaterial (white solid, yield 4%). ¹H NMR (DMSO-d₆, 400 MHz): δ=12.93 (s,1H), 7.98 (d, J=7.1 Hz, 2H), 7.77-7.62 (m, 3H), 6.80 (s, 1H), 3.67 (tt,J=7.9, 7.9 Hz, 1H, partially obscured by the solvent peak), 2.12-2.03(m, 2H), 1.83-1.49 ppm (m, 6H), one exchangeable proton is not observed.LC/MS (Table 1, Method B) R_(t)=3.71 min; MS m/z: 316 [M+H]⁺.

Example #8.4-Cyclohexyl-2-[[4-(difluoromethoxy)benzoyl]amino]thiophene-3-carboxylicacid (Compound #11)

The title compound was synthesized according to the procedure describedin Example #1 using methyl 2-amino-4-cyclohexylthiophene-3-carboxylate(CAS: 10413-33-9) and 4-(difluoromethoxy)benzoyl chloride (CAS:57320-63-5) as starting materials (white solid, yield 20%). ¹H NMR(DMSO-d₆, 400 MHz): δ=13.47 (s, 1H), 12.53 (s, 1H), 8.02-7.97 (m, 2H),7.61-7.24 (m, 3H), 6.74 (s, 1H), 3.24-3.16 (m, 1H), 1.94 (d, J=10.9 Hz,2H), 1.80-1.71 (m, 3H), 1.41-1.18 ppm (m, 5H). LC/MS (Table 1, Method A)R_(t)=3.06 min; MS m/z: 396 [M+H]⁺.

Example #9. 2-Benzamido-5-chloro-4-cyclohexyl-thiophene-3-carboxylicacid (Compound #12)

The title compound was synthesized according to the procedure describedin Example #5 using methyl 2-amino-4-cyclohexylthiophene-3-carboxylate(CAS: 10413-33-9) as a starting material (off-white solid, yield 39%).¹H NMR (DMSO-d₆, 400 MHz): δ=13.95 (s, 1H), 12.42 (s, 1H), 7.92 (d,J=7.5 Hz, 2H), 7.74-7.61 (m, 3H), 3.61 (t, J=12.4 Hz, 1H), 2.05 (q,J=12.0 Hz, 2H), 1.81 (d, J=11.7 Hz, 2H), 1.74-1.63 (m, 3H), 1.34-1.18ppm (m, 3H). LC/MS (Table 1, Method C) R_(t)=3.02 min; MS m/z: 364[M+H]⁺.

Example #10.5-Chloro-4-cyclohexyl-2-[[4-(difluoromethoxy)benzoyl]amino]thiophene-3-carboxylicacid (Compound #13)

The title compound was synthesized according to the procedure describedin Example #5 using methyl 2-amino-4-cyclohexylthiophene-3-carboxylate(CAS: 10413-33-9) and 4-(difluoromethoxy)benzoyl chloride (CAS:57320-63-5) as starting materials (off-white solid, yield 32%). ¹H NMR(DMSO-ds, 400 MHz): δ=13.98 (s, 1H), 12.46 (s, 1H), 8.02 (d, J=8.7 Hz,2H), 7.67-7.28 (m, 3H), 3.64 (t, J=10.9 Hz, 1H), 2.08 (q, J=11.6 Hz,2H), 1.85 (d, J=9.7 Hz, 2H), 1.78-1.67 (m, 3H), 1.39-1.25 ppm (m, 3H).LC/MS (Table 1, Method A) R_(t)=3.11 min; MS m/z: 430 [M+H]⁺.

Example #11.5-Chloro-4-cyclohexyl-2-[(2-methylbenzoyl)amino]thiophene-3-carboxylicacid (Compound #14)

The title compound was synthesized according to the procedure describedin Example #5 using methyl 2-amino-4-cyclohexylthiophene-3-carboxylate(CAS: 10413-33-9) and 2-methyl benzoyl chloride (CAS: 933-88-0) asstarting materials (white solid, yield 35%). ¹H NMR (DMSO-d₆, 400 MHz):δ=13.83 (s, 1H), 11.89 (s, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.4Hz, 1H), 7.46-7.39 (m, 2H), 3.60 (t, J=12.0 Hz, 1H), 2.51 (s, 3H), 2.07(q, J=11.7 Hz, 2H), 1.88-1.63 (m, 5H), 1.37-1.21 ppm (m 3H). LC/MS(Table 1, Method A) R_(t)=3.06 min: MS m/z: 378 [M+H]⁺.

Example #12.5-Chloro-4-cyclohexyl-2-[(4-morpholinobenzoyl)amino]thiophene-3-carboxylicacid (Compound #15)

To a solution of methyl5-chloro-4-cyclohexyl-2-(4-morpholinobenzamido)thiophene-3-carboxylate(Preparation #1, Step C, 145 mg, 0.31 mmol) was dissolved in THF (2.5ml) and MeOH (2.5 ml) was added lithium hydroxide monohydrate (CAS:1310-66-3, 66 mg, 1.57 mmol) and the reaction mixture was heated at 40°C. overnight. The mixture was cooled to RT and diluted with DCM and a 1Naqueous HCl solution. The two phases were separated and the aqueousphase was extracted with DCM (×2). The combined organic phases werepassed through a phase separator and the solvent was removed underreduced pressure. Purification by RP-HPLC (Table 2, Method A) afforded2-benzamido-4-(4-chloro-3-fluoro-phenyl)thiophene-3-carboxylic acid asan off-white solid (72.8 mg, yield 19%). ¹H NMR (DMSO-d₆, 400 MHz):δ=13.55 (s, 1H), 7.60 (d, J=9.2 Hz, 2H), 7.02 (br s, 1H), 6.91 (d, J=8.8Hz, 2H), 3.66-3.54 (m, 5H), 3.11 (dd, J=4.5, 4.5 Hz, 4H), 1.88 (q,J=11.4 Hz, 2H), 1.62-1.39 (m, 5H), 1.16-1.02 ppm (m, 3H). LC/MS (Table1, Method A) R_(t)=2.99 min; MS m/z: 449 [M+H]⁺.

Example #13. 2-Benzamido-5-chloro-4-cyclopentyl-thiophene-3-carboxylicacid (Compound #18)

The title compound was synthesized according to the procedure describedin Preparation #1, Step C and Example #12 using ethyl2-benzamido-4-cyclopentylthiophene-3-carboxylate (prepared as describedin Example #7) as a starting material (white solid, yield 11%). ¹H NMR(DMSO-d₆, 400 MHz): δ=13.91 (br s, 1H), 12.58 (br s, 1H), 7.93 (d, J=7.2Hz, 2H), 7.72 (dd, J=7.3, 7.3 Hz, 1H), 7.64 (dd, J=7.4, 7.4 Hz, 2H),3.96-3.85 (m, 1H), 2.01-1.95 (m, 2H), 1.85-1.84 (m, 4H), 1.67-1.61 (m2H). LC/MS (Table 1, Method A) R_(t)=2.94 min: MS m/z: 350 [M+H]⁺.

Example #14.2-Benzamido-4-[4-(trifluoromethyl)phenyl]thiophene-3-carboxylic acid(Compound #20)

The title compound was synthesized according to the procedure describedin Example #2 using 1-[4-(trifluoromethyl)phenyl]ethanone (CAS:709-63-7) as a starting material (off-white solid, yield 6%). ¹H NMR(DMSO-d₆, 400 MHz): δ=12.83 (br s, 1H), 8.02 (d, J=7.3 Hz, 2H),7.79-7.73 (m, 3H), 7.73-7.62 (m, 4H), 7.11 (s, 1H), one exchangeableproton is not observed. LC/MS (Table 1, Method B) R_(t)=3.70 min; MSm/z: 392 [M+H]⁺.

Example #15. 2-Benzamido-4-(p-tolyl)thiophene-3-carboxylic acid(Compound #21)

The title compound was synthesized according to the procedure describedin Example #2 using 1-(4-methylphenyl)ethanone (CAS: 122-00-9) as astarting material (white solid, yield 19%). ¹H NMR (DMSO-d₆, 400 MHz):δ=13.97 (br s, 1H), 8.02 (d, J=7.1 Hz, 2H), 7.73-7.63 (m, 3H), 7.30 (d,J=8.1 Hz, 2H), 7.18 (d, J=7.8 Hz, 2H), 6.83 (s, 1H), 2.38 (s, 3H). LC/MS(Table 1, Method A) R_(t)=2.82 min; MS m/z: 338 [M+H]⁺.

Example #16. 2-Benzamido-4-(3,4-dimethylphenyl)thiophene-3-carboxylicacid (Compound #22)

The title compound was synthesized according to the procedure describedin Example #2 using 1-(3,4-dimethylphenyl)ethanone (CAS: 3637-01-2) as astarting material (white solid, yield 6%). ¹H NMR (DMSO-d₆, 400 MHz):δ=12.56 (br s, 1H), 8.01 (d, J=7.3 Hz, 2H), 7.79-7.73 (m, 1H), 7.69 (dd,J=7.5, 7.5 Hz, 2H), 7.19-7.13 (m, 2H), 7.10 (d, J=7.8 Hz, 1H), 6.92 (s,1H), 2.29 (s, 6H), one exchangeable proton is not observed. LC/MS (Table1, Method A) R_(t)=2.83 min; MS m/z: 352 [M+H]⁺.

Example #17.2-Benzamido-5-chloro-4-(3,4-dimethylphenyl)thiophene-3-carboxylic acid(Compound #23)

The title compound was synthesized according to the procedure describedin Example #5 using 1-(3,4-dimethylphenyl)ethanone (CAS: 3637-01-2) as astarting material (white solid, yield 4%). ¹H NMR (DMSO-d₆, 400 MHz):δ=13.85 (br s, 1H), 8.00 (d, J=7.3 Hz, 2H), 7.76-7.69 (m, 1H), 7.66 (dd,J=7.3, 7.3 Hz, 2H), 7.19 (d, J=7.8 Hz, 1H), 7.07 (s, 1H), 7.02 (d, J=7.6Hz, 1H), 2.30 (s, 3H), 2.29 (s, 3H), one exchangeable proton is notobserved. LC/MS (Table 1, Method A) R_(t)=2.96 min; MS m/z: 386 [M+H]⁺.

Example #18. 2-Benzamido-5-chloro-4-(p-tolyl)thiophene-3-carboxylic acid(Compound #24)

The title compound was synthesized according to the procedures describedin Preparation 1, Step C and Example #12 using ethyl2-benzamido-4-(p-tolyl)thiophene-3-carboxylate (prepared as described inExample #15) as a starting material (white solid, yield 65%). ¹H NMR(DMSO-d₆, 400 MHz): δ=15.04 (br s, 1H), 7.98-7.95 (m, 2H), 7.65-7.56 (m,3H), 7.20-7.12 (m, 5H), 2.36 (s, 3H). LC/MS (Table 1, Method A)R_(t)=2.91 min; MS m/z: 372 [M+H]⁺.

Example #19.4-Cyclohexyl-2-[(3,4-dimethoxybenzoyl)amino]thiophene-3-carboxylic acid(Compound #25)

The title compound was synthesised according to the procedure describedin Example #1 using methyl 2-amino-4-cyclohexylthiophene-3-carboxylate(CAS: 10413-33-9) and 3,4-dimethoxybenzoyl chloride (CAS: 3535-37-3) asstarting materials (off-white solid, yield 72%). ¹H NMR (DMSO-d₆, 400MHz): δ=13.52-13.51 (br s, 1H), 12.58-12.56 (br s, 1H), 7.53-7.48 (m,2H), 7.20 (d, J=8.3 Hz, 1H), 6.70 (s, 1H), 3.88 (2×s, 6H), 3.23-3.19 (s,1H), 1.97-1.93 (m, 2H), 1.81-1.71 (m, 3H), 1.39-1.20 (m, 5H). LC/MS(Table 1, Method B) R_(t)=3.76 min; MS m/z: 390 [M+H]⁺.

Example #20. 2-Benzamido-4-cyclohexyl-thiophene-3-carboxylic acid(Compound #26)

The title compound was synthesised according to the procedure describedin Example #2 using 1-cyclohexylethan-1-one (CAS: 823-76-7) as astarting material (light yellow solid, yield 31%). ¹H NMR (DMSO-d₆, 400MHz): δ=13.50 (s, 1H), 12.58 (s, 1H), 7.96-7.92 (m, 2H), 7.71-7.61 (m,3H), 6.74 (s, 1H), 3.24-3.17 (m, 1H), 1.95-1.93 (m, 2H), 1.81-1.70 (m,3H), 1.37-1.20 (m, 5H). LC/MS (Table 1, Method A) R_(t)=2.80 min; MSm/z: 330 [M+H]⁺.

Example #21. 2-Benzamido-4-cyclohexyl-5-methyl-thiophene-3-carboxylicacid (Compound #27)

The title compound was synthesised according to the procedure describedin Example #2 using 1-cyclohexylpropan-1-one (CAS: 1123-86-0) as astarting material (off-white solid, yield 4%). ¹H NMR (CDCl₃, 400 MHz):δ=12.18 (br s, 1H), 7.98 (d, J=7.6 Hz, 2H), 7.60-7.45 (m, 3H), 3.49-3.43(m, 1H), 2.45 (s, 3H), 1.84-1.81 (m, 6H), 1.43-1.24 (m, 4H), oneexchangeable proton is not observed. LC/MS (Table 1, Method A)R_(t)=2.86 min; MS m/z: 344 [M+H]⁺.

Example #22.2-[[4-(Difluoromethoxy)benzoyl]amino]-4-phenyl-thiophene-3-carboxylicacid (Compound #28)

The title compound was synthesised according to the procedure describedin Example #1 using ethyl 2-amino-4-phenylthiophene-3-carboxylate (CAS:4815-36-5) and 4-(difluoromethoxy)benzoyl chloride (CAS: 57320-63-5) asstarting materials (white solid, yield 20%). ¹H NMR (DMSO-d₆, 400 MHz):δ=13.20 (s, 1H), 12.48 (s, 1H), 8.04-8.01 (m, 2H), 7.45-7.43 (m, 2H),7.44 (t, J=73.4 Hz, 1H), 7.38-7.36 (m, 5H), 6.96 (s, 1H). LC/MS (Table1, Method A) R_(t)=2.78 min; MS m/z: 390 [M+H]⁺.

Example #23.4-Cyclohexyl-2-[(4-morpholinobenzoyl)amino]thiophene-3-carboxylic acid(Compound #29)

The title compound was synthesised according to the procedure describedin Example #1 using 1-cyclohexylethan-1-one (CAS: 823-76-7) and4-morpholinobenzoyl chloride (CAS: 162848-18-2) as starting materials(white solid, yield 4%). ¹H NMR (DMSO-d₆, 400 MHz): δ=7.73 (d, J=8.8 Hz,2H), 7.00 (d, J=8.8 Hz, 2H), 6.44 (s, 1H), 3.71-3.65 (m, 4H), 3.23-3.20(m, 5H partially obscured by the water peak), 1.88-1.85 (m, 2H),1.73-1.62 (m, 3H), 1.20-1.14 (m, 5H). Two exchangeable protons notobserved. LC/MS (Table 1, Method A) R_(t)=2.81 min; MS m/z: 415 [M+H]⁺.

Example #24.2-[[4-(Difluoromethoxy)benzoyl]amino]-5-methyl-4-phenyl-thiophene-3-carboxylicacid (Compound #30)

The title compound was synthesised according to the procedure describedin Example #1 using methyl2-amino-5-methyl-4-phenylthiophene-3-carboxylate (CAS: 350988-88-4) and4-(difluoromethoxy)benzoyl chloride (CAS: 57320-63-5) as startingmaterials (white solid, yield 45%). ¹H NMR (DMSO-d₆, 400 MHz):δ=12.97-12.92 (s, 1H), 12.51-12.47 (s, 1H), 8.03-7.99 (m, 2H), 7.62-7.25(m, 6H), 7.24-7.21 (m, 2H), 2.13 (s, 3H). LC/MS (Table 1, Method A)R_(t)=2.86 min; MS m/z: 404 [M+H]⁺.

Example #25.5-Chloro-2-[[4-(difluoromethoxy)benzoyl]amino]-4-phenyl-thiophene-3-carboxylicacid (Compound #31)

The title compound was then synthesised according to the proceduredescribed in Example #5 using ethyl2-amino-4-phenyl-thiophene-3-carboxylate (CAS: 4815-36-5) and4-(difluoromethoxy)benzoyl chloride (57320-63-5) as starting materials(white solid, yield 21%). ¹H NMR (DMSO-d₆, 400 MHz): δ=13.40 (br s, 1H),8.06 (d, J=8.8 Hz, 2H), 7.49-7.40 (m, 6H), 7.34-7.28 (m, 2H), oneexchangeable proton is not observed. LC/MS (Table 1, Method A)R_(t)=2.96 min; MS m/z: 424 [M+H]⁺.

Example #26. 2-Benzamido-4-tert-butyl-thiophene-3-carboxylic acid(Compound #32)

The title compound was synthesised according to the procedure describedin Example #1 using ethyl 2-amino-4-tert-butylthiophene-3-carboxylate(CAS: 827614-39-1) as a starting material (white solid, yield 45%). ¹HNMR (DMSO-d₆, 400 MHz): δ 13.80 (br s, 1H), 12.31 (s, 1H), 7.97 (d,J=7.3 Hz, 2H), 7.74-7.61 (m, 3H), 6.84 (s, 1H), 1.45 (s, 9H). LC/MS(Table 1, Method A) R_(t)=2.67 min; MS m/z: 304 [M+H]⁺.

Example #27. 2-Benzamido-5-chloro-4-phenyl-thiophene-3-carboxylic acid(Compound #33)

The title compound was then synthesised according to the proceduredescribed in Example #5 using ethyl2-amino-4-phenyl-thiophene-3-carboxylate (CAS: 4815-36-5) as a startingmaterial (white solid, yield 21%). ¹H NMR (DMSO-d₆, 400 MHz): δ=13.32(br s, 1H), 12.93 (br s, 1H), 8.01 (d, J=7.3 Hz, 2H), 7.78-7.66 (m, 3H),7.50-7.41 (m, 3H), 7.35-7.31 (m, 2H). LC/MS (Table 1, Method A)R_(t)=2.85 min; MS m/z: 358 [M+H]⁺.

Example #28. 2-Benzamido-5-methyl-4-phenyl-thiophene-3-carboxylic acid(Compound #34)

The title compound was synthesised according to the procedure describedin Example #1 using methyl2-amino-5-methyl-4-phenylthiophene-3-carboxylate (CAS: 350988-88-4) as astarting material (white solid, yield 43%). ¹H NMR (DMSO-d₆, 400 MHz):δ=12.95 (s, 1H), 12.48-12.48 (s, 1H), 7.97-7.93 (m, 2H), 7.71-7.62 (m,3H), 7.41-7.32 (m, 3H), 7.24-7.20 (m, 2H), 2.13 (s, 3H). LC/MS (Table 1,Method C) R_(t)=5.10 min; MS m/z: 338 [M+H]⁺.

Example #29.2-Benzamido-4-(3,3-difluorocyclobutyl)thiophene-3-carboxylic acid(Compound #35)

The title compound was synthesised according to the procedure describedin Example #2 using 1-(3,3-difluorocyclobutyl)ethan-1-one (CAS:1621223-57-1) as a starting material (white solid, yield 6%). ¹H NMR(DMSO-d₆, 400 MHz): δ=13.69 (s, 1H), 12.54 (s, 1H), 7.99 (d, J=7.1 Hz,2H), 7.79-7.66 (m, 3H), 7.05 (s, 1H), 3.81-3.72 (m, 1H), 3.04-2.92 (m,2H), 2.77-2.66 (m, 2H). LC/MS (Table 1, Method A) R_(t)=2.70 min; MSm/z: 338 [M+H]⁺.

Example #30. 2-Benzamido-4-(3-chlorophenyl)thiophene-3-carboxylic acid(Compound #36)

The title compound was synthesised according to the procedure describedin Example #2 using 1-(3-chlorophenyl)ethanone (CAS: 99-02-5) as astarting material (off-white solid, yield 17%). ¹H NMR (DMSO-d₆, 400MHz): δ=13.35 (s, 1H), 12.52 (s, 1H), 8.01 (d, J=7.3 Hz, 2H), 7.78-7.67(m, 3H), 7.48-7.35 (m, 4H), 7.09 (s, 1H). LC/MS (Table 1, Method A)R_(t)=2.78 min; MS m/z: 358 [M+H]⁺.

Example #31. 2-Benzamido-4-norcaran-7-yl-thiophene-3-carboxylic acid(Compound #37)

A solution of bicyclo[4.1.0]heptane-7-carboxylic acid (CAS: 21448-77-1,2.00 g, 14.27 mmol) was dissolved in DMF (18 ml) was treated with DIPEA(CAS: 7087-68-5, 7.5 ml, 42.80 mmol), HATU (CAS: 148893-10-1, 8.14 g,21.40 mmol) and N,O-dimethylhydroxylamine hydrochloride (CAS: 6638-79-5,1.81 g, 18.55 mmol). The reaction mixture was stirred at RT for 2 hours.The reaction mixture was diluted with EtOAc and brine and the two phaseswere separated. The organic phase was washed with brine (×3), dried overMgSO₄ and the solvent was removed under reduced pressure. Purificationby flash chromatography on silica gel (eluting with 0-20% EtOAc inisohexane) affordedN-methoxy-N-methylbicyclo[4.1.0]heptane-7-carboxamide as an oil (2.6 g,yield quant.). To a stirred solution ofN-methoxy-N-methylbicyclo[4.1.0]heptane-7-carboxamide (2.6 g, 14.19mmol) in diethyl ether (30 ml) was added a solution of methylmagnesiumbromide in Et₂O (CAS: 75-16-1, 3.0 M, 11.8 ml, 35.48 mmol) and thereaction mixture was stirred at RT for 1.0 hour. The reaction wasquenched with a saturated aqueous NH₄Cl solution and the two phases wereseparated. The aqueous phase was extracted with diethyl ether. Thecombined organic phases were dried over MgSO₄ and the solvent wasremoved under reduced pressure to afford1-(bicyclo[4.1.0]heptan-7-yl)ethan-1-one an oil (1.96 g, yield quant.).1-(Bicyclo[4.1.0]heptan-7-yl)ethan-1-one (1.96 g, 14.18 mmol) wasdissolved in ethanol (15 ml) and then ethyl cyanoacetate (CAS: 105-56-6,1.5 ml, 14.18 mmol), sulfur (CAS: 7704-34-9, 455 mg, 14.18 mmol) andmorpholine (CAS: 110-91-8, 3.7 ml, 42.54 mmol) were added. The reactionmixture was heated at 80° C. for 16 hours and then it was allowed tocool to RT. The volatiles were removed under reduced pressure and theresidue was partitioned between EtOAc and brine and the two phases wereseparated. The organic phase was washed with brine, dried over MgSO₄ andthe solvent was removed under reduced pressure. Purification by flashchromatography on silica gel (eluting with 0-20% EtOAc in isohexane)afforded ethyl2-amino-4-(bicyclo[4.1.0]heptan-7-yl)thiophene-3-carboxylate as an oil(1.3 g, yield 35%). The title compound was synthesised according to theprocedure described in Example #1 using ethyl2-amino-4-(bicyclo[4.1.0]heptan-7-yl)thiophene-3-carboxylate as astarting material (yellow solid, yield 3%). ¹H NMR (DMSO-d₆, 400 MHz):δ=13.51 (s, 1H), 12.74 (s, 1H), 7.98 (d, J=7.8 Hz, 2H), 7.75-7.65 (m,3H), 6.54 (s, 1H), 2.18 (t, J=4.8, 1H), 2.00-1.88 (m, 2H), 1.84-1.74 (m,2H), 1.37-1.22 (m, 4H), 1.21-1.18 (m, 2H). LC/MS (Table 1, Method A)R_(t)=2.84 min; MS m/z: 342 [M+H]⁺.

Example #32. 2-Benzamido-4-(4-methoxyphenyl)thiophene-3-carboxylic acid(Compound #38)

The title compound was synthesised according to the procedure describedin Example #1 using ethyl2-amino-4-(4-methoxyphenyl)thiophene-3-carboxylate (CAS: 15854-11-2) asa starting material (off-white solid, yield 73%). ¹H NMR (DMSO-d₆, 400MHz): δ=13.22 (s, 1H), 12.52 (s, 1H), 8.01 (d, J=7.1 Hz, 2H), 7.79-7.68(m, 3H), 7.33 (d, J=8.8 Hz, 2H), 6.98 (d, J=7.8 Hz, 2H), 6.94 (s, 1H),3.83 (s, 3H). LC/MS (Table 1, Method A) R_(t)=2.68 min; MS m/z: 354[M+H]⁺.

Example #33.2-Benzamido-4-(2,2,3,3-tetramethylcyclopropyl)thiophene-3-carboxylicacid (Compound #39)

The title compound was synthesised according to the procedure describedin Example #31 using 2,2,3,3-tetramethylcyclopropanecarboxylic acid(CAS: 15641-58-4) as a starting material (white solid, yield 2%). ¹H NMR(DMSO-d₆, 400 MHz): δ=13.41 (s, 1H), 12.61 (s, 1H), 7.98 (d, J=7.3 Hz,2H), 7.77-7.71 (m, 1H), 7.71-7.64 (m, 2H), 6.74 (s, 1H), 1.55 (s, 1H),1.24 (s, 6H), 0.97 (s, 6H). LC/MS (Table 1, Method B) R_(t)=3.90 min; MSm/z: 344 [M+H]⁺.

Example #34. 2-Benzamido-4-methyl-5-phenyl-thiophene-3-carboxylic acid(Compound #40)

The title compound was synthesised according to the procedure describedin Example #1 using ethyl2-amino-4-methyl-5-phenylthiophene-3-carboxylate (CAS: 4815-38-7) as astarting material (white solid, yield 43%). ¹H NMR (DMSO-d₆, 400 MHz):δ=13.67 (br s, 1H), 12.70 (br s, 1H), 7.97-7.93 (m, 2H), 7.71-7.62 (m,3H), 7.51-7.40 (m, 5H), 2.39 (s, 3H). LC/MS (Table 1, Method C)R_(t)=5.28 min; MS m/z: 338 [M+H]⁺.

Example #35.5-Cyclohexyl-2-[[4-(difluoromethoxy)benzoyl]amino]thiophene-3-carboxylicacid (Compound #41)

The title compound was synthesised according to the procedure describedin Example #1 using methyl 2-amino-5-cyclohexylthiophene-3-carboxylate(CAS: 1350623-54-9) and 4-(difluoromethoxy)benzoyl chloride (CAS:57320-63-5) as starting materials (white solid, yield 27%). ¹H NMR(DMSO-d₆, 400 MHz): δ=12.51 (s, 1H), 8.00-7.97 (m, 2H), 7.43-7.39 (m,2H), 7.42 (t, J=73.1 Hz, 1H), 7.13 (br s, 1H), 6.91 (d, J=1.2 Hz, 1H),2.77-2.68 (m 1H), 2.00-1.95 (m, 2H), 1.82-1.75 (m, 2H), 1.71-1.67 (m,1H), 1.43-1.35 (m, 5H). LC/MS (Table 1, Method B) R_(t)=3.91 min; MSm/z: 396 [M+H]⁺.

Example #36. 2-[(2-Methylbenzoyl)amino]-4-phenyl-thiophene-3-carboxylicacid (Compound #42)

The title compound was synthesised according to the procedure describedin Example #1 using ethyl 2-amino-4-phenylthiophene-3-carboxylate (CAS:4815-36-5) and 2-methylbenzoyl chloride (CAS: 933-88-0) as startingmaterials (white solid, yield 55%). ¹H NMR (DMSO-d₆, 400 MHz): δ=13.09(s, 1H), 11.87 (s, 1H), 7.68-7.65 (m, 1H), 7.53-7.48 (m, 1H), 7.42-7.33(m, 7H), 6.94 (s, 1H), 2.49 (s, 3H, partially obscured by solvent peak).LC/MS (Table 1, Method C) R_(t)=4.99 min; MS m/z: 366 [M−H]⁻.

Example #37. 2-Benzamido-4-phenyl-thiophene-3-carboxylic acid (Compound#43)

The title compound was synthesised according to the procedure describedin Example #1 using ethyl 2-amino-4-phenylthiophene-3-carboxylate (CAS:4815-36-5) as a starting material (white solid, yield 17%). ¹H NMR(DMSO-d₆, 400 MHz): δ=13.24 (s, 1H), 12.51 (s, 1H), 8.04-8.00 (m, 2H),7.77-7.67 (m, 3H), 7.43-7.40 (m, 5H), 7.00 (s, 1H). LC/MS (Table 1,Method A) R_(t)=2.65 min; MS m/z: 324 [M+H]⁺.

Example #38. 2-Benzamido-4-(2-chlorophenyl)thiophene-3-carboxylic acid(Compound #44)

The title compound was synthesised according to the procedure describedin Example #1 using ethyl2-amino-4-(2-chlorophenyl)thiophene-3-carboxylate (CAS: 325724-66-1) asa starting material (off-white solid, yield 53%). ¹H NMR (DMSO-d₆, 400MHz): δ=13.13 (s, 1H), 12.46 (s, 1H), 8.01 (d, J=7.1 Hz, 2H), 7.79-7.66(m, 3H), 7.55-7.51 (m, 1H), 7.43-7.39 (m, 3H), 7.03 (s, 1H). LC/MS(Table 1, Method B) R_(t)=2.71 min; MS m/z: 358 [M+H]⁺.

Example #39. 2-[(2-Methylbenzoyl)amino]-5-phenyl-thiophene-3-carboxylicacid (Compound #45)

The title compound was synthesised according to the procedure describedin Example #1 using ethyl 2-amino-5-phenylthiophene-3-carboxylate (CAS:4815-34-3) and 2-methylbenzoyl chloride (CAS: 933-88-0) as startingmaterials (white solid, yield 27%). ¹H NMR (DMSO-d₆, 400 MHz): δ=13.51(br s, 1H), 11.63 (s, 1H), 7.72-7.67 (m, 3H), 7.59 (s, 1H), 7.51 (t,J=6.9 Hz, 1H), 7.47-7.37 (m, 4H), 7.32 (t, J=7.2 Hz, 1H), 2.51 (s, 3Hpartially obscured by solvent peak). LC/MS (Table 1, Method C)R_(t)=5.27 min; MS m/z: 338 [M+H]⁺.

Example #40.2-[(3,4-Dimethoxybenzoyl)amino]-4-phenyl-thiophene-3-carboxylic acid(Compound #46)

The title compound was synthesised according to the procedure describedin Example #1 using ethyl 2-amino-4-phenylthiophene-3-carboxylate (CAS:4815-36-5) and 3,4-dimethoxybenzoic acid (CAS: 93-07-2) as startingmaterials (off-white solid, yield 23%). ¹H NMR (DMSO-d₆, 400 MHz):δ=8.16 (s, 1H), 7.59-7.53 (m, 2H), 7.39-7.26 (m, 5H), 7.18 (d, J=8.3 Hz,1H), 6.74 (s, 1H), 3.88-3.87 (m, 6H), one exchangeable proton is notobserved. LC/MS (Table 1, Method B) R_(t)=2.64 min: MS m/z: 384 [M+H]⁺.

Example #41.2-Benzamido-4-(trans-4-tert-butylcyclohexyl)thiophene-3-carboxylic acid(Compound #48)

The title compound was then synthesized according to the proceduredescribed in Example #1 using ethyl2-amino-4-(trans-4-tert-butylcyclohexyl)thiophene-3-carboxylate as astarting material (white solid, yield 3%). Ethyl2-amino-4-(trans-4-tert-butylcyclohexyl)thiophene-3-carboxylate wasprepared according to the procedure described in Example #31 usingtrans-4-tert-butylcyclohexane-1-carboxylic acid (CAS: 943-29-3) as astarting material. ¹H NMR (DMSO-d₆, 400 MHz): δ=12.77 (s, 1H), 7.97-7.93(m, 2H), 7.73-7.61 (m, 3H), 6.72 (s, 1H), 3.15 (t, J=11.4 Hz, 1H), 2.02(d, J=11.7 Hz, 2H), 1.84 (d, J=10.5 Hz, 2H), 1.36-1.25 (m, 2H),1.16-1.01 (m, 3H), 0.88 (s, 9H), one exchangeable proton is notobserved. LC/MS (Table 1, Method A) R_(t)=3.22 min; MS m/z: 386 [M+H]⁺.

Example #42.2-Benzamido-5-chloro-4-[4-(trifluoromethyl)phenyl]thiophene-3-carboxylicacid (Compound #50)

The title compound was synthesized according to the procedure describedin Example #5 using 1-[4-(trifluoromethyl)phenyl]ethanone (CAS:709-63-7) as a starting material (white solid, yield 2%). ¹H NMR(DMSO-d₆, 400 MHz): δ=14.60 (br s, 1H), 8.02 (d, J=7.0 Hz, 2H), 7.80 (d,J=8.2 Hz, 2H), 7.74-7.61 (m, 3H), 7.55 (d, J=8.0 Hz, 2H), oneexchangeable proton is not observed. LC/MS (Table 1, Method A)R_(t)=3.14 min: MS m/z: 424 [M+H]⁺.

Example #43.2-Benzamido-4-(cis-4-tert-butylcyclohexyl)thiophene-3-carboxylic acid(Compound #54)

The title compound was then synthesized according to the proceduredescribed in Example #1 using ethyl2-amino-4-(cis-4-tert-butylcyclohexyl)thiophene-3-carboxylate as astarting material (white solid, yield 2%). Ethyl2-amino-4-(cis-4-tert-butylcyclohexyl)thiophene-3-carboxylate wasprepared as described in Example #41 usingcis-4-tert-butylcyclohexane-1-carboxylic acid (CAS: 943-28-2) as astarting material. ¹H NMR (DMSO-d₆, 400 MHz): δ=12.79 (s, 1H), 7.98 (d,J=7.4 Hz, 2H), 7.77-7.64 (m, 3H), 6.75 (s, 1H), 3.18 (t, J=11.7 Hz, 1H),2.05 (d, J=11.6 Hz, 2H), 1.87 (d, J=9.6 Hz, 2H), 1.41-1.26 (m, 2H),1.24-1.05 (m, 3H), 0.91 (s, 9H), one exchangeable proton is notobserved. LC/MS (Table 1, Method A) R_(t)=3.24 min; MS I/z: 386 [M+H]⁺.

Example #44.4-Cyclopentyl-2-[(4-morpholinobenzoyl)amino]thiophene-3-carboxylic acid(Compound #59)

To a solution of ethyl 2-amino-4-cyclopentylthiophene-3-carboxylate(prepared as described in Example #7, 800 mg, 3.34 mmol) in DCM (40 ml)was added DIPEA (CAS: 7087-68-5, 1.2 ml, 6.69 mmol) and 4-bromobenzoylchloride (CAS: 98-88-4, 880 mg, 4.01 mmol). The reaction mixture wasstirred at RT overnight. The resulting mixture was diluted with DCM andthe organic phase was washed with a 2N aqueous HCl solution, brine,dried over MgSO₄ and the solvent was removed under reduced pressure.Purification by flash chromatography on silica gel (eluting with 0-15%EtOAc in isohexane) afforded ethyl2-(4-bromobenzamido)-4-cyclopentylthiophene-3-carboxylate as a yellowsolid (1.12 g, yield 79%). Ethyl2-(4-bromobenzamido)-4-cyclopentylthiophene-3-carboxylate (150 mg, 0.355mmol), morpholine (CAS: 110-91-8, 47 μL, 0.533 mmol), RuPhos Pd G2 (CAS:1375325-68-0, 55 mg, 0.071 mmol) and Cs₂CO₃ (CAS: 534-17-8, 174 mg,0.533 mmol) were suspended in dioxane (3.0 ml) and the reaction mixturewas degassed with nitrogen for 5 minutes. The reaction mixture washeated at 80° C. for 3 h, allowed to cool to RT and diluted with DCM.The reaction mixture was filtered through a pad of Celite® and thesolvent was removed under reduced pressure. Purification by flashchromatography on silica gel (eluting with 0-40% EtOAc in isohexane)afforded ethyl4-cyclopentyl-2-(4-morpholinobenzamido)thiophene-3-carboxylate as ayellow solid (131 mg, yield 86%). The residue was dissolved in THF (2.2ml), MeOH (2.2 ml), water (1.5 ml) and lithium hydroxide monohydrate (64mg, 1.5 mmol) was added. The reaction mixture was stirred at 50° C.overnight. The mixture was allowed to cool to RT, diluted with EtOAc andwashed with a 1N aqueous HCl solution and brine. The organic phase wasdried over MgSO₄ and the solvent was removed under reduced pressure. Thesolid was triturated with MeOH, filtered and dried in vacuo to afford4-Cyclopentyl-2-[(4-morpholinobenzoyl)amino]thiophene-3-carboxylic acidas an off-white solid (100 mg, yield 82%). ¹H NMR (DMSO-d₆, 400 MHz):δ=13.46 (br s, 1H), 12.46 (s, 1H), 7.83 (d, J=8.7 Hz, 2H), 7.16 (d,J=8.4 Hz, 2H), 6.76 (s, 1H), 3.83-3.79 (m, 4H), 3.66-3.56 (m, 1H),3.35-3.32 (m, 4H, partially obscured by the water peak), 2.10-2.02 (m,2H), 1.80-1.51 (m, 6H). LC/MS (Table 1, Method A) R_(t)=2.93 min; MSm/z: 401 [M+H]⁺.

Example #45. 4-Cyclopentyl-2-[[4-(tetrahydropyran-4-ylamino)benzoyl]amino]thiophene-3-carboxylic acid (Compound #60)

The title compound was then synthesized according to the proceduredescribed in Example #44 using 4-aminotetrahydropyran (CAS: 38041-19-9)as a starting material (light yellow solid, yield 50%). ¹H NMR (DMSO-d₆,400 MHz): δ=13.38 (br s, 1H), 12.35 (s, 1H), 7.70 (d, J=8.8 Hz, 2H),6.79 (d, J=8.8 Hz, 2H), 6.72 (s, 1H), 6.59 (d, J=7.7 Hz, 1H), 3.93 (d,J=11.6 Hz, 2H), 3.68-3.57 (m, 2H), 3.49 (t, J=11.6 Hz, 2H), 2.10-1.93(m, 4H), 1.83-1.41 (m, 8H). LC/MS (Table 1, Method A) Rt=2.92 min; MSm/z: 415 [M+H]⁺.

Example #46.4-Cyclopentyl-2-[[4-(2-methoxyethylamino)benzoyl]amino]thiophene-3-carboxylicacid (Compound #61)

The title compound was then synthesized according to the proceduredescribed in Example #44 using 2-methoxyethanamine (CAS: 109-85-3) as astarting material (light yellow solid, yield 35%). ¹H NMR (DMSO-d₆, 400MHz): δ=13.39 (br s, 1H), 12.35 (s, 1H), 7.70 (d, J=8.6 Hz, 2H),6.81-6.65 (m, 4H), 3.65-3.53 (m, 3H), 3.36-3.30 (m, 5H, partiallyobscured by the water peak), 2.10-1.99 (m, 2H), 1.81-1.51 (m, 6H). LC/MS(Table 1, Method A) Rt=2.91 min; MS m/z: 398 [M+H]⁺.

Example #47.4-Cyclopentyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylicacid (Compound #62)

The title compound was then synthesize according to the proceduredescribed in Example #44 using 3-methoxyazetidine hydrochloride (CAS:148644-09-1) as a starting material (white solid, yield 67%). ¹H NMR(DMSO-d₆, 400 MHz): δ=13.45 (br s, 1H), 12.43 (s, 1H), 7.78 (d, J=8.7Hz, 2H), 6.74 (s, 1H), 6.61 (d, J=8.8 Hz, 2H), 4.45-4.38 (m, 1H), 4.22(t, J=7.4 Hz, 2H), 3.81 (dd, J=3.7, 8.9 Hz, 2H), 3.65-3.56 (m, 1H), 3.32(s, 3H), 2.10-2.02 (m, 2H), 1.80-1.49 (m, 6H). LC/MS (Table 1, Method A)Rt=2.96 min; MS m/z: 401 [M+H]⁺.

Example #48. 2-Benzamido-4-(3-phenylcyclobutyl)thiophene-3-carboxylicacid (Compound #63)

To a stirred solution of ethyl2-amino-4-(3-phenylcyclobutyl)thiophene-3-carboxylate ((preparedaccording to the procedure outlined in Example #31 using3-phenylcyclobutane-1-carboxylic acid (CAS: 66016-28-2) as a startingmaterial, 240 mg, 0.80 mmol)) in DCM (5.0 ml) was added DIPEA (CAS:7087-68-5, 0.42 ml, 2.39 mmol) and benzoyl chloride (CAS: 98-88-4, 0.12ml, 1.04 mmol). The reaction mixture was stirred at RT overnight. Theresulting mixture was diluted with DCM and the organic phase was washedsequentially with a 2N aqueous HCl solution and brine The organic phasewas dried over MgSO₄ and the solvent was removed under reduced pressure.Purification by flash chromatography on silica gel (eluting with 0-20%EtOAc in isohexane) afforded ethyl2-benzamido-4-(3-phenylcyclobutyl)thiophene-3-carboxylate (220 mg, yield68%). The title compound was then synthesized according to the proceduredescribed in Example #12 using ethyl2-benzamido-4-(3-phenylcyclobutyl)thiophene-3-carboxylate as a startingmaterial (white solid, yield 24%). ¹H NMR (DMSO-d₆, 400 MHz): δ=13.65(br s, 1H), 7.97-7.94 (m, 2H), 7.70-7.59 (m, 3H), 7.36-7.16 (m, 5H),4.05-3.89 (m, 1H), 3.59-3.41 (m, 1H), 2.77-2.69 (m, 2H), 2.15-2.04 (m,2H), one exchangeable proton is not observed. LC/MS (Table 1, Method A)R_(t)=3.11 min; MS m/z: 378 [M+H]⁺.

Example #49. 4-Cyclopentyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylic acid (Compound #66)

The title compound was then synthesized according to the proceduredescribed in Example #44 using tetrahydropyran-4-ylmethanamine (CAS:130290-79-8) as a starting material (white solid, yield 39%). ¹H NMR(DMSO-d₆, 400 MHz): δ=13.34 (br s, 1H), 12.28 (s, 1H), 7.66 (d, J=8.9Hz, 2H), 6.74-6.67 (m, 4H), 3.88 (dd, J=2.9, 11.2 Hz, 2H), 3.61-3.51 (m,1H), 3.29 (dt, J=1.9, 11.7 Hz, 2H), 3.02 (t, J=6.0 Hz, 2H), 2.05-1.97(m, 2H), 1.86-1.46 (m, 9H), 1.23 (dq, J=4.4, 12.3 Hz, 2H). LC/MS (Table1, Method A) Rt=2.95 min; MS m/z: 429 [M+H]+.

Example #50.4-Cyclopentyl-2-[(3-morpholinobenzoyl)amino]thiophene-3-carboxylic acid(Compound #71)

The title compound was synthesized according to the procedure describedin Example #23, using ethyl 2-amino-4-cyclopentylthiophene-3-carboxylate(prepared as described in Example #10) and 3-morpholinobenzoyl chloride(CAS: 221876-07-9) as starting materials (off-white solid, yield 26%).3-Morpholinobenzoyl chloride was prepared from 3-morpholinobenzoic acid(CAS: 215309-00-5) using the procedure outlined in WO2001027089. ¹H NMR(DMSO-d₆, 400 MHz): δ=13.60 (br s, 1H), 12.51 (s, 1H), 7.55-7.47 (m,2H), 7.39-7.31 (m, 2H), 6.82 (s, 1H), 3.83 (t, J=4.3 Hz, 4H), 3.61 (tt,J=7.9, 7.9 Hz, 1H), 3.28-3.25 (m, 4H), 2.10-2.00 (m, 2H), 1.80-1.51 (m,6H). LC/MS (Table 1, Method A) R_(t)=2.76 min; MS m/z: 401 [M+H]⁺.

Example #51. 2-Benzamido-4-chroman-3-yl-thiophene-3-carboxylic acid(Compound #84)

The title compound was synthesized according to the procedure describedin Example #1, using ethyl2-amino-4-(chroman-3-yl)thiophene-3-carboxylate as a starting material(white solid, yield 9%). Ethyl2-amino-4-(chroman-3-yl)thiophene-3-carboxylate was prepared asdescribed in Example #31 using chromane-3-carboxylic acid (CAS:115822-57-6) as a starting material ¹H NMR (DMSO-d₆, 400 MHz): δ=13.84(br s, 1H), 12.55 (s, 1H), 7.99 (d, J=7.3 Hz, 2H), 7.79-7.66 (m, 3H),7.20-7.12 (m, 2H), 6.95-6.82 (m, 3H), 4.43 (d, J=10.0 Hz, 1H), 4.06-3.91(m, 2H), 3.13-3.03 (m, 2H). LC/MS (Table 1, Method B) R_(t)=3.65 min; MSm/z: 380 [M+H]⁺.

Example #52. 2-Benzamido-4-chroman-2-yl-thiophene-3-carboxylic acid(Compound #85)

The title compound was synthesized according to the procedure describedin Example #1, using ethyl2-amino-4-(chroman-2-yl)thiophene-3-carboxylate as a starting material(light yellow solid, yield 69%). Ethyl2-amino-4-(chroman-2-yl)thiophene-3-carboxylate was prepared asdescribed in Example #31 using chromane-2-carboxylic acid (CAS:51939-71-0) as a starting material. ¹H NMR (DMSO-d₆, 400 MHz): δ=13.85(br s, 1H), 12.49 (s, 1H), 7.99 (d, J=7.2 Hz, 2H), 7.79-7.64 (m, 3H),7.20-7.11 (m, 2H), 7.06 (s, 1H), 6.94-6.89 (m, 2H), 5.62 (d, J=8.7 Hz,1H), 2.99-2.87 (m, 1H), 2.82-2.71 (m, 1H), 2.44-2.34 (m, 1H), 1.96-1.82(m, 1H). LC/MS (Table 1, Method A) Rt=2.92 min: MS m/z: 380 [M+H]⁺.

Example #53. 2-Benzamido-4-cyclopropyl-thiophene-3-carboxylic acid(Compound #87)

The title compound was synthesized according to the procedure describedin Example #1, using ethyl 2-amino-4-cyclopropylthiophene-3-carboxylate(CAS: 120109-75-3) as a starting material (white solid, yield 48%). ¹HNMR (DMSO-d₆, 400 MHz): δ=13.53 (br s, 1H), 12.75 (br s, 1H), 7.99 (d,J=7.1 Hz, 2H), 7.77-7.65 (m, 3H), 6.60 (s, 1H), 2.49-2.42 (m, 1H),0.92-0.85 (m, 2H), 0.68-0.62 (m, 2H). LC/MS (Table 1, Method B)R_(t)=3.44 min; MS m/z: 286 [M−H]⁻.

Example #54.4-Cyclopropyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylicacid (Compound #88)

The title compound was synthesized according to the procedure describedin Example #44, using ethyl 2-amino-4-cyclopropylthiophene-3-carboxylate(CAS: 120109-75-3) and 3-methoxyazetidine hydrochloride (CAS:148644-09-1) as starting materials (yellow solid, yield 45%). ¹H NMR(DMSO-d₆, 400 MHz): δ=13.41 (br s, 1H), 12.38 (s, 1H), 7.78 (d, J=8.5Hz, 2H), 6.61 (d, J=8.3 Hz, 2H), 6.53 (s, 1H), 4.44-4.39 (m, 1H), 4.23(t, J=7.2 Hz, 2H), 3.82 (dd, J=3.7, 8.7 Hz, 2H), 3.32 (s, 3H), 2.43-2.37(m, 1H), 0.90-0.83 (m, 2H), 0.67-0.61 (m, 2H). LC/MS (Table 1, Method B)R_(t)=3.46 min; MS m/z: 373 [M+H]⁺.

Example #55.4-Cyclopropyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylicacid (Compound #90)

The title compound was synthesized according to the procedure describedin Example #44, using ethyl 2-amino-4-cyclopropylthiophene-3-carboxylate(CAS: 120109-75-3) and tetrahydropyran-4-ylmethanamine (CAS:130290-79-8) as starting materials (white solid, yield 39%). ¹H NMR(DMSO-d₆, 400 MHz): δ=13.41 (br s, 1H), 12.50 (s, 1H), 7.70 (d, J=8.8Hz, 2H), 6.78-6.68 (m, 3H), 6.48 (s, 1H), 3.93 (d, J=11.2 Hz, 2H), 3.33(t, J=11.5 Hz, 2H), 3.06 (t, J=5.9 Hz, 2H), 2.49-2.41 (m, 1H), 1.91-1.81(m, 1H), 1.71 (d, J=13.1 Hz, 2H), 1.28 (ddt, J=3.9, 12.1, 12.2 Hz, 2H),0.90-0.83 (m, 2H), 0.67-0.59 (m, 2H). LC/MS (Table 1, Method A)R_(t)=3.46 min; MS m/z: 401 [M+H]⁺.

Example #56.4-Tert-butyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylicacid (Compound #91)

The title compound was synthesized according to the procedure describedin Example #44 using ethyl2-(4-bromobenzamido)-4-(tert-butyl)thiophene-3-carboxylate (Preparation#2) and tetrahydropyran-4-ylmethanamine (CAS: 130290-79-8) as startingmaterials (white solid, yield 37%). ¹H NMR (CDCl₃, 400 MHz): δ=12.24 (s,1H), 7.80 (d, J=8.5 Hz, 2H), 6.59-6.52 (m, 3H), 4.00 (dd, J=3.3, 11.3Hz, 2H), 3.38 (t, J=11.6 Hz, 2H), 3.06 (d, J=6.8 Hz, 2H), 1.90-1.79 (m,1H), 1.68 (d, J=12.6 Hz, 2H), 1.49-1.30 (m, 11H), two exchangeableprotons are not observed. LC/MS (Table 1, Method B) R_(t)=3.58 min; MSm/z: 417 [M+H]⁺.

Example #57.4-tert-Butyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylicacid (Compound #92)

The title compound was synthesized according to the procedure describedin Example #44 using ethyl2-(4-bromobenzamido)-4-(tert-butyl)thiophene-3-carboxylate (Preparation#2) and 3-methoxyazetidine hydrochloride (CAS: 148644-09-1) as startingmaterials (white solid, yield 25%). ¹H NMR (CDCl₃, 400 MHz): δ=12.19 (s,1H), 7.82 (d, J=8.6 Hz, 2H), 6.56 (s, 1H), 6.37 (d, J=8.4 Hz, 2H),4.38-4.32 (m, 1H), 4.11 (t, J=7.2 Hz, 2H), 3.79 (dd, J=4.1, 8.4 Hz, 2H),3.35 (s, 3H), 1.46 (s, 9H), one exchangeable proton not observed. LC/MS(Table 1, Method A) R_(t)=2.76 min: MS m/z: 389 [M+H]⁺.

Example #58.4-Chroman-3-yl-2-[[4-(2-methoxyethoxy)benzoyl]amino]thiophene-3-carboxylicacid (Compound #95)

The title compound was synthesized according to the procedure describedin Example #50 using ethyl2-amino-4-(chroman-3-yl)thiophene-3-carboxylate (prepared as describedin Example #51) and 4-(2-methoxyethoxy)benzoic acid (CAS: 27890-92-2) asstarting materials (white solid, yield 2%). ¹H NMR (DMSO-d₆, 400 MHz):δ=13.80 (br s, 1H), 7.93-7.87 (m, 2H), 7.30-7.07 (m, 5H), 6.85 (dt,J=1.2, 7.4 Hz, 1H), 6.81-6.77 (m, 1H), 6.74 (s, 1H), 4.42-4.36 (m, 1H),4.23-4.20 (m, 2H), 4.12-3.93 (m, 2H), 3.73-3.69 (m, 2H), 3.34 (s, 3H),3.05-2.99 (m, 2H). LC/MS (Table 1, Method B) R_(t)=3.62 min; MS m/z: 454[M+H]⁺.

Example #59. 2-Benzamido-4-isobutyl-thiophene-3-carboxylic acid(Compound #96)

The title compound was synthesized according to the procedure describedin Example #2 using 4-methyl-2-pentanone as a starting material (whitesolid, yield 5%). ¹H NMR (CDCl₃, 400 MHz): δ=12.23 (s, 1H), 8.01 (d,J=7.6 Hz, 2H), 7.62 (t, J=7.4 Hz, 1H), 7.53 (t, J=7.6 Hz, 2H), 6.48 (s,1H), 2.74 (d, J=6.9 Hz, 2H), 2.01-1.90 (m, 1H), 0.96 (d, J=6.6 Hz, 6H),one exchangeable proton is not observed. LC/MS (Table 1, Method A)R_(t)=2.78 min; MS m/z: 304 [M+H]⁺.

Example #60.4-Cyclobutyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylicacid (Compound #97)

The title compound was synthesized according to the procedure describedin Example #44, using ethyl 2-amino-4-cyclobutylthiophene-3-carboxylate(Preparation #3) and 3-methoxyazetidine hydrochloride (CAS: 148644-09-1)as starting materials (yellow solid, yield 32%). ¹H NMR (CDCl₃, 400MHz): δ=12.03 (s, 1H), 7.87 (d, J=8.6 Hz, 2H), 6.52-6.44 (m, 3H),4.41-4.34 (m, 1H), 4.18 (t, J=7.2 Hz, 2H), 3.95-3.81 (m, 3H), 3.36 (s,3H), 2.42-2.34 (m, 2H), 2.15-1.82 (m, 4H), one exchangeable proton isnot observed. LC/MS (Table 1, Method A) R_(t)=2.79 min; MS m/z: 387[M+H]⁺.

Example #61. 2-Benzamido-4-cyclobutyl-thiophene-3-carboxylic acid(Compound #98)

The title compound was then synthesized according to the proceduredescribed in Example #1 using ethyl2-amino-4-cyclobutylthiophene-3-carboxylate (Preparation #3) as astarting material (white solid, yield 23%). ¹H NMR (CDCl₃, 400 MHz):δ=12.18 (s, 1H), 8.02-7.98 (m, 2H), 7.64-7.50 (m, 3H), 6.57 (s, 1H),3.92 (tt, J=8.3, 8.4 Hz, 1H), 2.44-2.35 (m, 2H), 2.15-1.81 (m, 4H), oneproton not observed. LC/MS (Table 1, Method B) R_(t)=3.62 min; MS m/z:302 [M+H]⁺.

Example #62.4-Cyclobutyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylicacid (Compound #99)

The title compound was synthesized according to the procedure describedin Example #44, using ethyl 2-amino-4-cyclobutylthiophene-3-carboxylate(Preparation #3) and tetrahydropyran-4-ylmethanamine (CAS: 130290-79-8)as starting materials (white solid, yield 26%). ¹H NMR (DMSO-d₆, 400MHz): δ=13.34 (br s, 1H), 12.48 (br s, 1H), 7.70 (d, J=8.6 Hz, 2H),6.79-6.68 (m, 4H), 3.93-3.87 (m, 3H), 3.35 (t, J=11.8 Hz, 2H, partiallyobscured by the water peak), 3.06 (t, J=6.0 Hz, 2H), 2.37-2.29 (m, 2H),2.11-1.70 (m, 7H), 1.33-1.22 (m, 2H). LC/MS (Table 1, Method B)R_(t)=3.58 min: MS m/z: 415 [M+H]⁺.

Example #63.2-[[4-(3-Methoxyazetidin-1-yl)benzoyl]amino]-4,5-dimethyl-thiophene-3-carboxylicacid (Compound #100)

The title compound was synthesized according to the procedure describedin Example #44, using ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate(CAS: 4815-24-1) and 3-methoxyazetidine hydrochloride (CAS: 148644-09-1)as starting materials (white solid, yield 15%). ¹H NMR (DMSO-d₆, 400MHz): δ=12.83 (s, 1H), 7.78 (d, J=8.6 Hz, 2H), 7.20 (br s, 1H), 6.58 (d,J=8.7 Hz, 2H), 4.45-4.36 (m, 1H), 4.19 (dd, J=6.7, 7.9 Hz, 2H), 3.79(dd, J=3.8, 8.5 Hz, 2H), 3.32 (s, 3H), 2.29 (s, 6H). LC/MS (Table 1,Method B) R_(t)=3.45 min; MS m/z: 361 [M+H]⁺.

Example #64.4,5-Dimethyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylicacid (Compound #102)

The title compound was synthesized according to the procedure describedin Example #44, using ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate(CAS: 4815-24-1) and tetrahydropyran-4-ylmethanamine (CAS: 130290-79-8)as starting materials (white solid, yield 29%). ¹H NMR (DMSO-d₆, 400MHz): δ=12.56 (br s, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.22 (br s, 1H), 6.70(d, J=8.8 Hz, 2H), 6.64 (t, J=5.5 Hz, 1H), 3.87 (dd, J=3.1, 11.3 Hz,2H), 3.29 (dt, J=1.8, 11.7 Hz, 2H), 3.01 (t, J=6.1 Hz, 2H), 2.25 (s,6H), 1.86-1.77 (m, 1H), 1.68 (d, J=12.8 Hz, 2H), 1.23 (ddt, J=4.2, 12.2,12.3 Hz, 2H). LC/MS (Table 1, Method B) R_(t)=3.39 min; MS m/z: 389[M+H]⁺.

Example #65.4-tert-Butyl-2-[[4-(2-methoxyethylamino)benzoyl]amino]thiophene-3-carboxylicacid (Compound #103)

The title compound was synthesized according to the procedure describedin Example #44 using ethyl2-(4-bromobenzamido)-4-(tert-butyl)thiophene-3-carboxylate (Preparation#2) and 2-methoxyethanamine (CAS: 109-85-3) as starting materials (whitesolid, yield 62%). ¹H NMR (CDCl₃, 400 MHz): δ=12.24 (s, 1H), 7.84 (d,J=8.8 Hz, 2H), 6.65 (d, J=8.5 Hz, 2H), 6.57 (s, 1H), 3.65 (t, J=4.9 Hz,2H), 3.42 (s, 3H), 3.37 (t, J=5.1 Hz, 2H), 1.47 (s, 9H), twoexchangeable protons not observed. LC/MS (Table 1, Method D) R_(t)=5.02min; MS m/z: 377 [M+H]⁺.

Example #66.4-tert-Butyl-2-[[4-(3-ethoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylicacid (Compound #104)

The title compound was synthesized according to the procedure describedin Example #44 using ethyl2-(4-bromobenzamido)-4-(tert-butyl)thiophene-3-carboxylate (Preparation#2) and 3-ethoxyazetidine hydrochloride (CAS: 88536-21-4) as startingmaterials (white solid, yield 43%). ¹H NMR (CDCl₃, 400 MHz): δ=12.20 (s,1H), 7.85 (d, J=8.6 Hz, 2H), 6.58 (s, 1H), 6.41 (d, J=8.5 Hz, 2H),4.49-4.41 (m, 1H), 4.16 (t, J=7.1 Hz, 2H), 3.82 (dd, J=4.4, 8.3 Hz, 2H),3.51 (q, J=7.0 Hz, 2H), 1.47 (s, 9H), 1.25 (t, J=7.0 Hz, 3H), oneexchangeable proton not observed. LC/MS (Table 1, Method E) R_(t)=3.38min; MS m/z: 403 [M+H]⁺.

Example #67.4-tert-Butyl-2-[[4-(tetrahydropyran-4-ylamino)benzoyl]amino]thiophene-3-carboxylicacid (Compound #105)

The title compound was synthesized according to the procedure describedin Example #44 using ethyl2-(4-bromobenzamido)-4-(tert-butyl)thiophene-3-carboxylate (Preparation#2) and 4-aminotetrahydropyran (CAS 38041-19-9) as starting materials(white solid, yield 28%). ¹H NMR (CDCl₃, 400 MHz): δ=12.20 (s, 1H), 7.78(d, J=8.6 Hz, 2H), 6.58-6.53 (m, 3H), 4.04-3.97 (m, 2H), 3.55-3.47 (m,3H), 2.01 (d, J=12.2 Hz, 2H), 1.56-1.44 (m, 11H), two exchangeableprotons are not observed. LC/MS (Table 1, Method E) R_(t)=3.12 min: MSm/z: 403 [M+H]⁺.

Example #68.4-(3,3-Difluorocyclobutyl)-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylicacid (Compound #106)

The title compound was synthesized according to the procedure describedin Example #44, using ethyl2-amino-4-(3,3-difluorocyclobutyl)thiophene-3-carboxylate (Preparation#4) and tetrahydropyran-4-ylmethanamine (CAS: 130290-79-8) as startingmaterials (white solid, yield 34%). ¹H NMR (DMSO-d₆, 400 MHz): δ=13.53(br s, 1H), 12.30 (s, 1H), 7.71 (d, J=8.7 Hz, 2H), 6.93 (s, 1H),6.81-6.74 (m, 3H), 3.96-3.89 (m, 2H), 3.77-3.71 (m, 1H), 3.38-3.30 (m,2H, partially obscured by the water peak), 3.10-2.91 (m, 4H), 2.79-2.66(m, 2H), 1.92-1.71 (m, 3H), 1.35-1.24 (m, 2H). LC/MS (Table 1, Method E)R_(t)=3.32 min; MS m/z: 451 [M+H]⁺.

Example #69.4-(3,3-Difluorocyclobutyl)-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylicacid (Compound #107)

The title compound was synthesized according to the procedure describedin Example #44, using ethyl2-amino-4-(3,3-difluorocyclobutyl)thiophene-3-carboxylate (Preparation#4) and 3-methoxyazetidine hydrochloride (CAS: 148644-09-1) as startingmaterials (white solid, yield 45%). ¹H NMR (CDCl₃, 400 MHz): δ=12.04 (s,1H), 7.86 (d, J=8.5 Hz, 2H), 6.52-6.44 (m, 3H), 4.42-4.35 (m, 1H), 4.19(t, J=7.3 Hz, 2H), 3.89-3.74 (m, 3H), 3.36 (s, 3H), 3.07-2.95 (m, 2H),2.72-2.58 (m, 2H), one exchangeable proton is not observed. LC/MS (Table1, Method E) R_(t)=3.30 min: MS m/z: 423 [M+H]⁺.

Example #70.2-[[4-(2-Methoxyethylamino)benzoyl]amino]-4-(1-methylcyclopropyl)thiophene-3-carboxylicacid (Compound #108)

The title compound was synthesized according to the procedure describedin Example #44, using ethyl2-amino-4-(1-methylcyclopropyl)thiophene-3-carboxylate ((prepared asdescribed in Example #2 using 1-(1-methylcyclopropyl)ethan-1-one (CAS:1567-75-5) as a starting material)) and 2-methoxyethanamine (CAS:109-85-3) as starting materials (white solid, yield 8%). ¹H NMR(DMSO-d₆, 400 MHz): δ=13.32 (br s, 1H), 12.54 (br s, 1H), 7.67 (d, J=8.9Hz, 2H), 6.74 (d, J=8.9 Hz, 2H), 6.70 (s, 1H), 6.63 (t, J=5.6 Hz, 1H),3.52 (t, J=5.5 Hz, 2H), 3.34-3.26 (m, 5H), 1.34 (s, 3H), 0.76 (dd,J=4.4, 5.7 Hz, 2H), 0.62 (dd, J=4.5, 6.0 Hz, 2H). LC/MS (Table 1, MethodE) R_(t)=3.04 min; MS m/z: 373 [M+H]⁺.

Example #71.4-iso-Butyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylicacid diethylamine salt (Compound #109)

The title compound was synthesized according to the procedure describedin Example #44, using ethyl 2-amino-4-isobutylthiophene-3-carboxylate((prepared as described in Example #2 using 4-methyl-2-pentanone (CAS:108-10-1) as a starting material)) and 3-methoxyazetidine hydrochloride(CAS: 148644-09-1) as starting materials (white solid, yield 34%). ¹HNMR (DMSO-d₆, 400 MHz): δ=15.37 (s, 1H), 8.80 (s, 1H), 7.77 (d, J=8.9Hz, 2H), 6.52 (d, J=8.7 Hz, 2H), 6.30 (s, 1H), 4.40-4.33 (m, 1H),4.18-4.13 (m, 2H), 3.74 (dd, J=4.1, 8.7 Hz, 2H), 3.27 (s, 3H), 2.94 (q,J=7.2 Hz, 4H), 2.75 (d, J=6.9 Hz, 2H), 2.00-1.89 (m, 1H), 1.20 (t, J=7.3Hz, 6H), 0.85 (d, J=6.7 Hz, 6H). LC/MS (Table 1, Method D) R_(t)=5.42min: MS m/z: 389 [M+H]⁺.

Example #72.4-tert-Butyl-2-[[3-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylicacid (Compound #110)

The title compound was synthesized according to the procedure describedin Example #44, using ethyl2-amino-4-(tert-butyl)thiophene-3-carboxylate (CAS: 827614-39-1),3-bromobenzoyl chloride (CAS: 1711-09-7) andtetrahydropyran-4-ylmethanamine (CAS: 130290-79-8) as starting materials(white solid, yield 6%). ¹H NMR (DMSO-d₆, 400 MHz): δ=13.93 (br s, 1H),12.65 (br s, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.15 (s, 1H), 7.06 (d, J=7.3Hz, 1H), 6.88 (dd, J=1.5, 8.1 Hz, 1H), 6.77 (s, 1H), 6.14 (s, 1H), 3.91(dd, J=2.9, 10.9 Hz, 2H), 3.33 (t, J=11.4 Hz, 2H), 3.01 (d, J=6.6 Hz,2H), 1.91-1.80 (m, 1H), 1.74 (d, J=12.6 Hz, 2H), 1.45 (s, 9H), 1.28(ddt, J=4.1, 12.2, 12.2 Hz, 2H). LC/MS (Table 1, Method D) R_(t)=5.28min; MS m/z: 417 [M+H]⁺.

Example #73.4-(1-Methylcyclopropyl)-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylicacid (Compound #111)

The title compound was synthesized according to the procedure describedin Example #44, using ethyl2-amino-4-(1-methylcyclopropyl)thiophene-3-carboxylate ((prepared asdescribed in Example #2 using 1-(1-methylcyclopropyl)ethan-1-one (CAS:1567-75-5) as a starting material)) and tetrahydropyran-4-ylmethanamine(CAS: 130290-79-8) as starting materials (white solid, yield 12%). ¹HNMR (DMSO-d₆, 400 MHz): δ=12.89 (s, 1H), 7.71 (d, J=9.0 Hz, 2H),6.77-6.62 (m, 4H), 3.91 (dd, J=2.7, 11.2 Hz, 2H), 3.32 (t, J=11.1 Hz,2H), 3.05 (t, J=6.1 Hz, 2H), 1.90-1.78 (m, 1H), 1.71 (d, J=13.0 Hz, 2H),1.42-1.19 (m, 5H), 0.83-0.75 (m, 2H), 0.68-0.61 (m, 2H), oneexchangeable proton is not observed. LC/MS (Table 1, Method D)R_(t)=5.04 min; MS m/z: 415 [M+H]⁺.

Example #74.2-[[4-(3-Methoxyazetidin-1-yl)benzoyl]amino]-4-(1-methylcyclopropyl)thiophene-3-carboxylic acid (Compound #112)

The title compound was synthesized according to the procedure describedin Example #44, using ethyl2-amino-4-(1-methylcyclopropyl)thiophene-3-carboxylate ((prepared asdescribed in Example #2 using 1-(1-methylcyclopropyl)ethan-1-one (CAS:1567-75-5) as a starting material)) and 3-methoxyazetidine hydrochloride(CAS: 148644-09-1) as starting materials (white solid, yield 20%). ¹HNMR (DMSO-d₆, 400 MHz): δ=13.29 (br s, 1H), 12.51 (s, 1H), 7.75 (d,J=8.8 Hz, 2H), 6.73 (s, 1H), 6.60-6.54 (m, 2H), 4.40-4.34 (m, 1H), 4.17(dd, J=6.6, 8.5 Hz, 2H), 3.77 (dd, J=4.0, 9.0 Hz, 2H), 3.27 (s, 3H),1.33 (s, 3H), 0.80-0.74 (m, 2H), 0.66-0.60 (m, 2H). LC/MS (Table 1,Method E) R_(t)=3.23 min; MS m/z: 387 [M+H]⁺.

Example #75.4-Isobutyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylicacid (Compound #113)

The title compound was synthesized according to the procedure describedin Example #44, using ethyl 2-amino-4-isobutylthiophene-3-carboxylate((prepared as described in Example #2 using 4-methyl-2-pentanone (CAS:108-10-1) as a starting material)) and tetrahydropyran-4-ylmethanamine(CAS: 130290-79-8) as starting materials (yellow solid, yield 20%). ¹HNMR (DMSO-d₆, 400 MHz): δ=13.37 (br s, 1H), 12.35 (s, 1H), 7.74 (d,J=8.7 Hz, 2H), 6.83-6.66 (m, 4H), 3.95 (dd, J=2.7, 11.4 Hz, 2H),3.39-3.32 (m, 2H), 3.10 (t, J=6.0 Hz, 2H), 2.72 (d, J=6.9 Hz, 2H),1.99-1.85 (m, 2H), 1.76 (d, J=12.7 Hz, 2H), 1.38-1.25 (m, 2H), 0.95 (d,J=6.7 Hz, 6H). LC/MS (Table 1, Method D) R_(t)=5.29 min: MS m/z: 417[M+H]⁺.

Example #76.5-Isopropyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]-4-methyl-thiophene-3-carboxylicacid diethylamine salt (Compound #114)

The title compound was synthesized according to the procedure describedin Example #44, using ethyl2-amino-5-isopropyl-4-methylthiophene-3-carboxylate (minor regioisomer,prepared as described in Example #2 using 4-methyl-2-pentanone (CAS:108-10-1) as a starting material) and 3-methoxyazetidine hydrochloride(CAS: 148644-09-1) as starting materials (off-white solid, yield 15%).¹H NMR (DMSO-d₆, 400 MHz): δ=15.30 (br s, 1H), 8.59 (br s, 1H), 7.79 (d,J=8.7 Hz, 2H), 6.55 (d, J=8.5 Hz, 2H), 4.44-4.37 (m, 1H), 4.22-4.15 (m,2H), 3.77 (dd, J=3.9, 8.3 Hz, 2H), 3.33-3.25 (m, 4H), 2.96 (q, J=7.2 Hz,4H), 2.37 (s, 3H), 1.28-1.19 (m, 12H). LC/MS (Table 1, Method E)R_(t)=5.39 min; MS m/z: 389 [M+H]⁺.

Example #77.2-[[4-(3-Methoxyazetidin-1-yl)benzoyl]amino]-4-(1-methylcyclobutyl)thiophene-3-carboxylic acid (Compound #115)

To a stirred solution of 1-methylcyclobutane-1-carboxylic acid (CAS:32936-76-8, 4.5 ml, 43.8 mmol) in Et₂O (150 ml) at 0° C. was addeddropwise a solution of methyllithium in Et₂O (CAS: 917-54-4, 1.6M, 54.8ml, 87.6 mmol) over 2 hours. The reaction mixture was warmed at RT andstirred at RT for 5 hours. The reaction mixture was cooled at 0° C. andquenched with a 3N aqueous HCl solution. The two phases were separatedand the organic phase was washed with a saturated aqueous NaHCO₃solution and brine, dried over MgSO₄ and the solvent was removed underreduced pressure. Purification by flash chromatography on silica gel(eluting with 0-100% EtOAc in cyclohexane) afforded1-(1-methylcyclobutyl)ethan-1-one as a colorless oil (1.68 g, yield 34%,purity 42%). The residue (1.68 g, purity 42%) was dissolved in ethanol(30 ml) and then ethyl cyanoacetate (CAS: 105-56-6, 1.6 ml, 15.0 mmol)and morpholine (CAS: 110-91-8, 2.0 ml, 22.5 mmol) were added. Thereaction mixture was heated at 50° C. for 30 minutes and then sulfur(CAS: 7704-34-9, 530 mg, 16.5 mmol) was added. The reaction mixture washeated at 80° C. overnight and then allowed to cool to RT. The reactionwas next partitioned between EtOAc and brine. The two phases wereseparated and the aqueous phase was extracted with EtOAc. The combinedorganic phases were dried over MgSO₄ and the solvent was removed underreduced pressure. Purification by flash chromatography on silica gel(eluting with 0-100% EtOAc in cyclohexane) afforded ethyl2-amino-4-(1-methylcyclobutyl)thiophene-3-carboxylate as a yellow oil(220 mg, yield 6%). The title compound was then synthesized according tothe procedure described in Example #44, using ethyl2-amino-4-(1-methylcyclobutyl)thiophene-3-carboxylate and3-methoxyazetidine hydrochloride (CAS: 148644-09-1) as startingmaterials (white solid, yield 42%). ¹H NMR (DMSO-d₆, 400 MHz): δ=13.36(br s, 1H), 12.48 (br s, 1H), 7.78 (d, J=8.7 Hz, 2H), 6.63-6.58 (m, 3H),4.46-4.39 (m, 1H), 4.25-4.19 (m, 2H), 3.84-3.79 (m, 2H), 3.32 (s, 3H),2.43-2.34 (m, 2H), 2.16-2.02 (m, 3H), 1.78-1.71 (m, 1H), 1.53 (s, 3H).LC/MS (Table 1, Method E) R_(t)=3.39 min; MS m/z: 401 [M+H]⁺.

Example #78.4-tert-Butyl-2-[[4-(2-methoxyethoxy)benzoyl]amino]thiophene-3-carboxylicacid (Compound #116)

The title compound was synthesized according to the procedure describedin Example #44, using 4-(2-methoxyethoxy)benzoyl chloride (CAS:756478-87-2) and ethyl 2-amino-4-(tert-butyl)thiophene-3-carboxylate(CAS: 827614-39-1) as starting materials (white solid, yield 8%).4-(2-Methoxyethoxy)benzoyl chloride (CAS: 756478-87-2) was synthesizedaccording to the procedure described in Example #83 using4-(2-methoxyethoxy)benzoic acid (CAS: 27890-92-2) as a startingmaterial. ¹H NMR (DMSO-d₆, 400 MHz): δ=13.80 (br s, 1H), 12.35 (br s,1H), 7.91-7.85 (m, 2H), 7.19-7.12 (m, 2H), 6.75 (s, 1H), 4.23-4.20 (m,2H), 3.72-3.68 (m, 2H), 3.33 (s, 3H), 1.41 (s, 9H). LC/MS (Table 1,Method E) R_(t)=3.15 min; MS m/z: 376 [M+H]⁺.

Example #79. 4-tert-Butyl-2-[[4-[2-methoxyethyl(methyl)amino]benzoyl]amino]thiophene-3-carboxylic acid (Compound #117)

The title compound was synthesized according to the procedure describedin Example #44 using ethyl2-(4-bromobenzamido)-4-(tert-butyl)thiophene-3-carboxylate (Preparation#2) and 2-methoxy-N-methyl-ethanamine (CAS: 38256-93-8) as startingmaterials (white solid, yield 54%). ¹H NMR (CDCl₃, 400 MHz): δ=12.25 (s,1H), 7.82 (d, J=8.7 Hz, 2H), 6.70-6.41 (m, 3H), 3.54 (s, 4H), 3.33 (s,3H), 3.01 (s, 3H), 1.47 (s, 9H), one exchangeable proton is notobserved. LC/MS (Table 1, Method E) R_(t)=3.24 min; MS m/z: 391 [M+H]⁺.

Example #80.4-tert-Butyl-2-[[4-(tetrahydropyran-3-ylamino)benzoyl]amino]thiophene-3-carboxylicacid (Compound #118)

The title compound was synthesized according to the procedure describedin Example #44 using ethyl2-(4-bromobenzamido)-4-(tert-butyl)thiophene-3-carboxylate (Preparation#2) and tetrahydropyran-3-amine (CAS: 120811-32-7) as starting materials(white solid, yield 36%). ¹H NMR (CDCl₃, 400 MHz): δ=12.21 (s, 1H), 7.76(d, J=8.1 Hz, 2H), 6.59-6.52 (m, 3H), 3.89 (d, J=11.2 Hz, 1H), 3.75-3.63(m, 2H), 3.54-3.43 (m, 2H), 1.95-1.56 (m, 4H), 1.44 (s, 9H), twoexchangeable protons are not observed. LC/MS (Table 1, Method E)R_(t)=3.19 min; MS m/z: 403 [M+H]⁺.

Example #81.4-tert-Butyl-2-[[4-(tetrahydropyran-3-ylmethylamino)benzoyl]amino]thiophene-3-carboxylicacid (Compound #119)

The title compound was synthesized according to the procedure describedin Example #44 using ethyl2-(4-bromobenzamido)-4-(tert-butyl)thiophene-3-carboxylate (Preparation#2) and tetrahydropyran-3-ylmethanamine (CAS: 7179-99-9) as startingmaterials (white solid, yield 25%). ¹H NMR (CDCl₃, 400 MHz): δ=12.25 (s,1H), 7.81 (d, J=8.6 Hz, 2H), 6.61-6.55 (m, 3H), 3.95-3.80 (m, 2H),3.56-3.47 (m, 1H), 3.34 (dd, J=8.4, 11.0 Hz, 1H), 3.10 (dq, J=6.7, 14.6Hz, 2H), 1.98-1.87 (m, 2H), 1.74-1.32 (m, 12H), two exchangeable protonsare not observed. LC/MS (Table 1, Method E) R_(t)=3.32 min: MS m/z: 417[M+H]⁺.

Example #82.4-tert-Butyl-2-[[4-[methyl(tetrahydropyran-4-ylmethyl)amino]benzoyl]amino]thiophene-3-carboxylicacid (Compound #120)

The title compound was synthesized according to the procedure describedin Example #44 using ethyl2-(4-bromobenzamido)-4-(tert-butyl)thiophene-3-carboxylate (Preparation#2) and N-methyl-(tetrahydropyran-4-ylmethyl) (CAS: 439081-52-4) asstarting materials (white solid, yield 35%). ¹H NMR (CDCl₃, 400 MHz):δ=12.26 (s, 1H), 7.85 (d, J=8.6 Hz, 2H), 6.66 (d, J=8.9 Hz, 2H), 6.56(s, 1H), 3.99 (dd, J=3.4, 11.2 Hz, 2H), 3.39-3.23 (m, 4H, partiallyobscured by the water peak), 3.03 (s, 3H), 2.04-1.95 (m, 1H), 1.68-1.29(m, 13H), one exchangeable proton is not observed. LC/MS (Table 1,Method D) R_(t)=5.48 min; MS m/z: 431 [M+H]⁺.

Example #83.4-tert-Butyl-2-[[2-fluoro-4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylicacid(Compound #121)

To a stirred solution of 4-bromo-2-fluorobenzoic acid (CAS: 112704-79-7,750 mg, 3.42 mmol) in DCM (15 ml) at 0° C. was added DMF (0.3 μl, 0.004mmol) and oxalyl chloride (CAS: 79-37-8, 0.31 ml, 3.60 mmol). Thereaction mixture was allowed to warm to RT and stirred at RT for 2hours. A further aliquot of oxalyl chloride (0.31 ml, 3.60 mmol) wasadded and the reaction mixture was stirred at RT for additional 20hours. The solvent was removed under reduced pressure to afford4-bromo-2-fluorobenzoyl chloride (812 mg, yield quant.).4-Bromo-2-fluorobenzoyl chloride (200 mg, 0.84 mmol) was then added to astirred solution of ethyl 2-amino-4-(tert-butyl)thiophene-3-carboxylate(CAS: 827614-39-1, 147 mg, 0.65 mmol) and DIPEA (CAS: 7087-68-5, 0.34ml, 1.94 mmol) in DCM (5.0 ml) and the reaction mixture was stirred atRT for 20 hours. The resulting mixture was diluted with DCM and theorganic phase was washed sequentially with 1N aqueous HCl solution andbrine. The organic phase was passed through a phase separator and thesolvent was removed under reduced pressure. Purification by flashchromatography on silica gel (eluting with 0-20% EtOAc in isohexane)afforded ethyl2-(4-bromo-2-fluorobenzamido)-4-(tert-butyl)thiophene-3-carboxylate (220mg, yield 61%). The title compound was then synthesized according to theprocedure described in Example #44 using ethyl2-(4-bromo-2-fluorobenzamido)-4-(tert-butyl)thiophene-3-carboxylate and3-methoxyazetidine hydrochloride (CAS: 148644-09-1) as startingmaterials (white solid, yield 22%). ¹H NMR (DMSO-d₆, 400 MHz): δ=13.83(br s, 1H), 12.57 (br s, 1H), 7.87 (t, J=8.8 Hz, 1H), 6.72 (s, 1H),6.45-6.32 (m, 2H), 4.45-4.36 (m, 1H), 4.25-4.18 (m, 2H), 3.83 (dd,J=3.6, 8.8 Hz, 2H), 3.31 (s, 3H), 1.44 (s, 9H). LC/MS (Table 1, MethodD) R_(t)=5.39 min; MS m/z: 407 [M+H]⁺.

Example #84.2-Benzamido-4-(5,6,7,8-tetrahydroquinolin-2-yl)thiophene-3-carboxylicacid (Compound #195)

To a stirred solution of 5,6,7,8,-tetrahydroquinoline-2-carbonitrile(CAS: 150459-78-2, 2.5 g, 15.8 mmol) in THF (50 ml) at 0° C. was addeddropwise a solution of methylmagnesium bromide in Et₂O (CAS: 75-16-1,3.0M, 11 ml, 148.9 mmol). The reaction mixture was stirred at 0° C. for20 minutes and next allowed to warm to RT. The reaction was stirred atRT for 2 hours and again cooled to 0° C. The reaction was quenched with1M aqueous citric acid and next allowed to warm to RT. The reactionmixture was extracted with EtOAc (×3). The combined organic phases werewashed with brine and the solvent was removed under reduced pressure.Purification by flash chromatography on silica gel (eluting with 0-100%EtOAc in isohexane) afforded1-(5,6,7,8-tetrahydroquinolin-2-yl)ethan-1-one as a pale yellow solid(1.6 g, yield 57%). The title compound was then synthesized according tothe procedure described in Example #1 using1-(5,6,7,8-tetrahydroquinolin-2-yl)ethan-1-one and benzoyl chloride(CAS: 98-88-4) as starting materials (off-white solid, yield 7%). ¹H NMR(DMSO-d₆, 400 MHz): δ=14.31 (s, 1H), 8.13-8.10 (m, 2H), 7.72 (d, J=8.3Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.60-7.51 (m, 3H), 7.47 (s, 1H), 3.06(dd, J=6.3, 6.3 Hz, 2H), 2.84 (dd, J=6.1, 6.1 Hz, 2H), 2.01-1.86 (m,4H), one exchangeable proton not observed. LC/MS (Table 1, Method D)R_(t)=4.33 min, MS m/z: 379 [M+H]⁺.

Preparation #1. Methyl5-chloro-4-cyclohexyl-2-(4-morpholinobenzamido)thiophene-3-carboxylate

Step A. Methyl 2-(4-bromobenzamido)-4-cyclohexylthiophene-3-carboxylate

To a solution of methyl 2-amino-4-cyclohexylthiophene-3-carboxylate(CAS: 10413-33-9, 250 mg, 1.00 mmol) in DCM (10.0 ml) was added DIPEA(CAS: 7087-68-5, 400 μl, 2.00 mmol) and 4-bromobenzoyl chloride (CAS:586-75-4, 285 mg, 1.30 mmol). The reaction mixture was stirred at roomtemperature overnight. The resulting mixture was diluted with DCM and asaturated aqueous NaHCO₃ solution and the two phases were separated. Theorganic phase was washed sequentially with a 1N aqueous HCl solution andbrine, dried over MgSO₄ and the solvent was removed under reducedpressure. Tritutaration with EtOAc/isohexane afforded the title compoundas a yellow solid (330 mg, yield 75%). ¹H NMR (CDCl₃, 400 MHz): δ=12.45(s, 1H), 7.88 (d, J=8.5 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H), 6.49 (s, 1H),3.96 (s, 3H), 3.11 (t, J=11.3 Hz, 1H), 1.98-1.22 ppm (m, 10H).

Step B. Methyl4-cyclohexyl-2-(4-morpholinobenzamido)thiophene-3-carboxylate

Methyl 2-(4-bromobenzamido)-4-cyclohexylthiophene-3-carboxylate(Preparation #1, Step A, 330 mg, 0.78 mmol), morpholine (CAS: 110-91-8,100 μl, 1.17 mmol), RuPhos Pd G2 (CAS: 1375325-68-0, 121 mg, 0.16 mmol)and Cs₂CO₃ (CAS: 534-17-8, 382 mg, 1.17 mmol) were suspended in dioxane(6 ml) and the reaction mixture was degassed with nitrogen for 5minutes. The reaction mixture was heated at 75° C. overnight, cooled toRT and diluted with DCM. The mixture was filtered through a pad ofCelite®, and the solvents were removed under reduced pressure.Purification by flash chromatography on silica gel (eluting with 0-50%EtOAc in isohexane) afforded the title compound as a yellow solid (265mg, yield 79%). ¹H NMR (CDCl₃, 400 MHz): δ=12.29 (s, 1H), 7.94 (d, J=8.8Hz, 2H), 6.95 (d, J=8.5 Hz, 2H), 6.44 (s, 1H), 3.95 (s, 3H), 3.87 (dd,J=4.7, 4.7 Hz, 4H), 3.30 (dd, J=4.9, 4.9 Hz, 4H), 3.10 (t, J=11.5 Hz,1H), 1.97 (d, J=11.4 Hz, 2H), 1.85-1.72 (m, 3H), 1.46-1.24 ppm (m, 5H).

Step C. Methyl5-chloro-4-cyclohexyl-2-(4-morpholinobenzamido)thiophene-3-carboxylate

A solution of methyl5-chloro-4-cyclohexyl-2-(4-morpholinobenzamido)thiophene-3-carboxylate(Preparation #1, Step B, 100 mg, 0.23 mmol) in chloroform (7.0 ml) wastreated with N-chlorosuccinimide (CAS: 128-09-6, 31 mg, 0.23 mmol) andthe reaction mixture was stirred at RT for 5 minutes, at 40° C. for 1hour, at 50° C. for 2 hours and at 60° C. overnight. The reactionmixture was cooled to RT and partitioned between DCM and brine. The twophases were separated. The aqueous phase was extracted with DCM (×3).The combined organic phases were passed through a phase separator andthe solvent was removed under reduced pressure. Purification by flashchromatography on silica gel (eluting with 0-40% EtOAc in isohexane)afforded methyl5-chloro-4-cyclohexyl-2-(4-morpholinobenzamido)thiophene-3-carboxylateas an orange solid (107 mg, yield 99%). ¹H NMR (CDCl₃, 400 MHz): δ=12.22(s, 1H), 7.89 (d, J=9.1 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 3.95 (s, 3H),3.87 (dd, J=4.9, 4.9 Hz, 4H), 3.41 (t, J=11.2 Hz, 1H), 3.31 (dd, J=4.6,4.6 Hz, 4H), 2.08-1.65 (m, 6H), 1.37-1.24 ppm (m, 4H).

Preparation #2. Ethyl2-(4-bromobenzamido)-4-(tert-butyl)thiophene-3-carboxylate

The title compound was synthesized according to the procedure describedin Preparation #1, Step A, using ethyl2-amino-4-(tert-butyl)thiophene-3-carboxylate (CAS: 827614-39-1) as astarting material (yield 84%). ¹H NMR (CDCl₃, 400 MHz): δ=12.51 (br s,1H), 7.87 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.5 Hz, 2H), 6.62 (s, 1H), 4.48(q, J=7.2 Hz, 2H), 1.48 (t, J=7.3 Hz, 3H), 1.42 (s, 9H).

Preparation #3. Ethyl 2-amino-4-cyclobutylthiophene-3-carboxylate

Cyclobutyl methyl ketone (CAS: 3019-25-8, 1.5 ml, 13.51 mmol) wasdissolved in ethanol (70 ml) and then ethyl cyanoacetate (CAS: 105-56-6,1.6 ml, 14.86 mmol) and morpholine (CAS: 110-91-8, 1.3 ml, 14.86 mmol)were added. The reaction mixture was heated at 50° C. for 30 minutes andthen sulfur (CAS: 7704-34-9, 520 mg, 16.21 mmol) was added. The reactionmixture was heated at 80° C. overnight. The reaction was allowed to coolto RT and the volatiles were removed under reduced pressure. The residuewas partitioned between EtOAc and a saturated aqueous NaHCO₃ solutionand the two phases were separated. The aqueous phase was extracted withEtOAc (×2). The combined organic phases were dried over MgSO₄ and thesolvent was removed under reduced pressure. Purification by flashchromatography on silica gel (eluting with 0-30% EtOAc in isohexane)afforded ethyl 2-amino-4-cyclobutylthiophene-3-carboxylate as a yellowoil (829 mg, 27%). ¹H NMR (CDCl₃, 400 MHz): δ=6.04 (s, 2H), 5.91 (d,J=1.3 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 3.79-3.70 (m, 1H), 2.31-2.25 (m,2H), 2.03-1.52 (m, 4H), 1.37 (t, J=7.1 Hz, 3H).

Preparation #4. Ethyl2-amino-4-(3,3-difluorocyclobutyl)thiophene-3-carboxylate

The title compound was synthesized according to the procedure describedin Preparation #3, using 1-(3,3-difluorocyclobutyl)ethan-1-one (CAS:1621223-57-1) as a starting material (yield 36%). ¹H NMR (CDCl₃, 400MHz): δ=6.10 (br s, 2H), 5.91 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 3.66-3.57(m, 1H), 2.95-2.83 (m, 2H), 2.62-2.47 (m, 2H), 1.37 (t, J=7.1 Hz, 3H).

Example B—Biology Example B1—Antiviral Effect

The antiviral effect of the compounds of the invention have been testedon A549 cell lines infected with H1N1 (influenza A/New Caledonia/20/99).IC50 are reported in the following Table 1. The results show that thecompounds of the present invention present an antiviral effect.

TABLE 1 Com- IC50 Com- Com- pound (μM) pound IC50 (μM) pound IC50 (μM)#18 0.0648 #4 0.17 #10 0.2049 #9 0.21 #2 0.2105 #15 0.225 #12 0.2453 #60.2469 #5 0.26 #1 0.2978 #20 0.31 #24 0.35 #13 0.37 #11 0.4123 #23 0.42#14 0.5 #22 0.55 #21 0.61 #25 0.7289 #26 0.7451 #27 0.88 #28 1.27 #291.27 #30 1.37 #31 1.37 #32 1.47 #33 1.47 #34 1.4805 #35 1.67 #36 1.67#37 1.87 #38 1.87 #39 2.37 #40 2.47 #41 2.57 #42 5.8665 #43 5.95 #446.65 #45 8.55 #46 9.65 #48 0.35 #50 0.32 #54 0.46 #59 0.075 #60 0.047#61 0.1 #62 0.052 #63 0.15 #66 0.015 #71 0.13 #84 0.2871 #85 0.5062 #870.81 #88 0.5 #90 0.24 #91 0.12 #92 0.26 #95 0.61 #96 0.61 #97 0.11 #980.61 #99 0.014 #100 0.0445 #102 0.82 #103 0.46 #104 0.24 #105 0.68 #1060.35 #107 0.46 #108 0.56 #109 0.2 #110 0.82 #111 0.2 #112 0.38 #113 0.12#114 0.51 #115 0.24 #116 0.01 #117 0.076 #118 0.2 #119 0.1 #120 0.1 #1210.51

Materials & Methods

Human A549 cells (80,000 cells/well in a 96 well plate) were treatedwith a range of concentration of test compounds and immediately infectedby H1N1 A/New Caledonia/20/99 virus (clinical isolate) at MOI of 0.1 inDMEM/1% Penicillin/streptomycin supplemented with 0.25 g/ml TPCK trypsin(Sigma) and incubated at 37° C. in 5% CO2. 48 h post-infection,supernatants (25 μl) were collected and transferred into a 96-well blackflat-bottom plate, mixed with 25 μl PBS with Ca++/Mg++ (Thermo Fisher)and 50 μl of 2′-(4-Methylumbelliferyl)-ax-D-N-acetylneuraminic acidsodium salt hydrate stock-solution (20 μM, MUNANA, Sigma). Plates wereincubated 1h at 37° C. and reaction is stopped by adding 100 μl of StopSolution (glycine 0.1 M pH10.7/25% ethanol). The amount of fluorescentproduct released by MUNANA hydrolysis (4-MU) was measured in a Tecanspectrophotometer with excitation and emission wavelengths of 365 and450 nm respectively.

Example B2—Antitumoral Effect

Results

The cytotoxicity was tested for compounds of the invention on fivedifferent cell-lines, namely LXFL 1121, MAXF 401, MMXF L-636, PRXF PC-3Mand UXF 1138 which are respectively lung large cell carcinoma, breastadeno carcinoma, multiple myeloma, prostate adeno carcinoma and uterinesarcoma.The IC50 are provided in the following table 2

TABLE 2 Absolute IC50 (μM) Compound Cell Line #2 LXFL 1121 10,723 MAXF401 6,556 MMXF L-363 11,891 PRXF PC-3M 4,736 UXF 1138 4,478Therefore, the compounds have a cytotoxicity against tumor cells and canbe used for treating cancer.Materials and MethodsCompound HandlingA working stock solution of the test compounds was prepared in DMSO at aconcentration of 33 mM or 8.25 mM, and small aliquots were stored at−20° C. On each day of an experiment, a frozen aliquot of the workingstock solution was thawed and stored at room temperature prior to andduring treatment.All liquid handling steps were performed using the Tecan Freedom EVO 200platform. First, serial 2-fold dilutions of the 33 mM DMSO working stocksolution were done in DMSO. The DMSO dilutions were then diluted 1:22into cell culture medium in an intermediate dilution plate. Finally, 10μl taken from the intermediate dilution plate were transferred to 140μl/well of the final assay plate. Thus, the DMSO serial dilutions werediluted 1:330 with cell culture medium, and the DMSO concentration inthe assay was 0.3% v/v.Tumor Cell LinesThe cell lines used in this study were derived from solid tumors as wellas from hematological malignancies.Cell lines were routinely passaged once or twice weekly and maintainedin culture for up to 20 passages. Most cell lines were grown at 37° C.in a humidified atmosphere with 5% CO₂ in RPMI 1640 medium (25 mM HEPES,with L-glutamine, #FG1385, Biochrom, Berlin, Germany) supplemented with10% (v/v) fetal calf serum (Sigma, Taufkirchen, Germany) and 0.05 mg/mLgentamicin (Life Technologies, Karlsruhe, Germany).Propidium Iodide-Based Monolayer AssayA modified propidium iodide (PI) based monolayer assay was used toassess the anti-cancer activity of the compounds. Briefly, cells wereharvested from exponential phase cultures, counted and plated in 96 wellflat-bottom microtiter plates at a cell density of 4,000 to 40,000cells/well dependent on the cell line's growth rate. The individualseeding density for each cell line ensure exponential growth conditionsover the whole or at least the bigger part of the treatment period.After a 24 h recovery period, to allow the cells to resume exponentialgrowth, 10 μl of culture medium (6 control wells/cell line/plate) or ofculture medium with test compounds were added. Compounds were applied atten concentrations in 2-fold increments in duplicates up to 25 μM or 100μM and treatment continued for four days. After four days of treatment,cells were next washed with 200 μl PBS to remove dead cells and debris,then 200 μl of a solution containing 7 μg/ml propidium iodide (PI) and0.1% (v/v) Triton X-100 was added. After an incubation period of 1-2hours at room temperature, fluorescence (FU) was measured using theEnspire Multimode Plate Reader (excitation λ=530 nm, emission λ=620 nm)to quantify the amount of attached viable cells.Data EvaluationAn assay was considered fully evaluable if the following quality controlcriteria were fulfilled:

-   -   Z′-factor calculated within the assay plate ≥0.5    -   control/background ratio >3.0    -   coefficient of variation in the growth control wells ≤30%        Drug effects were expressed in terms of the percentage of the        fluorescence signal, obtained by comparison of the mean signal        in the treated wells with the mean signal of the untreated        controls (expressed by the test-versus-control value, T/C-value        [%]):

${\frac{T}{C}\lbrack\%\rbrack} = {\frac{{mean}{fluorescen}{ce}{signal}_{{treated}{group}}}{{mean}{fluorescen}{ce}{signal}_{{control}{group}}} \cdot 100}$IC values reported reflect the concentration of the test compound thatachieves T/C=50%. Calculation was done by 4 parameter non-linear curvefit.

Example B3—Modulators of NEET Proteins

The modulator effect on the NEET proteins encoded by human CISD1, CISD2,and CISD3 genes by the compounds of the invention has been tested and isreported below. Particularly, the biochemical function of the NEETproteins is measured by the stability of Fe—S cluster binding of thepurified NEET proteins.

The Fe—S cluster binding capacity of NEET proteins is known to becoordinated by four amino-acids in a stretch of 16 (three Cysteine andone Histidine). As the lability of the Fe—S cluster of NEET proteins issensitive to the environment, cluster stability measurements are one ofthe measures of interactions of NEET proteins with small molecules andcompounds. NEET protein/2Fe-2S cluster stability can be assessed bymonitoring the decay in absorbance of its characteristic 458-nm peak(characteristic of the oxidized 2Fe-2S cluster) over time. Each NEETprotein (mitoNEET, NAF-1 and Miner 2) was tested for its Fe—S binding inthe absence or presence of a compound according to the invention (seetable 3 below). The rate of cluster release (time in minutes to achieve50% loss of bound Fe—S cluster) was compared for each NEET protein inthe presence of one of the compounds of the invention (in a 1:3protein:compound molar ratio) relative to each protein alone.

At pH 6, all the three NEET proteins (mitoNEET, NAF-1 and Miner 2) havea characteristic rate of loss of the bound Fe—S cluster that can bemeasured by the decrease of absorbance at wavelength 458 nm over time,using a spectrophotometer. Thus, Bis-Tris buffer (100 mM Bis-Tris pH6,100 mM Nacl) was used at pH 6 to dilute either DMSO (Blank sample:Bis-Tris Buffer pH 6, 66 μM DMSO), DMSO and one of the three NEETproteins (Control sample: Bis-Tris Buffer pH 6, 66 μM DMSO, 20 μMpurified NEET protein) or DMSO, one of the three NEET proteins and acompound of the invention (Test sample: Bis-Tris Buffer pH 6, 66 μMDMSO, 20 μM purified NEET protein, 60 μM compound of the invention).

A reaction mix containing DMSO diluted in the Bis-Tris Buffer with orwithout a compound of the invention was prepared. The purified NEETprotein was the last component added to the reaction mix which was thenaliquoted into 4 replicates in 96 wells plates. The absorbance atwavelength 458 nm was taken at 5 minutes intervals at 37° C. with aspectrofluorimeter. The assay run time for CISD2 gene product (NAF-1)was 500 minutes and 180 minutes for both the CISD 1 gene product(mitoNEET) and the CISD3 gene product (Miner 2).

In addition to time monitoring, residual bound Fe—S cluster to NEETprotein was measured at the final point of the spectrometry assay foreach Test sample and compared to the Control sample data (in parenthesistable 3). This residual binding is measured by the differentialpercentage between the absorbance 458 nm at time zero and the absorbance458 nm at the end of the experiment (i.e. respectively 500 or 180minutes as described hereabove), showing the percentage of NEET proteinstill able to bind Fe—S cluster.

TABLE 3 Residual cluster bound at end of Time (in minutes) to achieve50% loss of experiment (Percentage Absorbance bound cluster (Absorbance458 nm), 458 nm at time zero) (Vehicle control (Vehicle control data inparenthesis) data in parenthesis) CISD1 CISD2 CISD3 CISD1 CISD2 CISD3Gene Gene Gene Gene Gene Gene Product Product Product Product ProductProduct Compound (mitoNEET) (NAF-1) (Miner2) (mitoNEET) (NAF-1) (DMSO11%)  #9 100 (80) 370 (310) 50% loss not 20% (16%) 17% (3%) 57% (11%)achieved during 180 minutes (60) #18 50% loss not 240 (310) 50% loss not52% (16%) 38% (3%) 69% (11%) achieved achieved during 180 during 180minutes (80) minutes (60) #26 105 (80) 355 (310) 50% loss not 36% (16%)18% (3%) 52% (11%) achieved during 180 minutes (60)  #2 50% loss not 50%loss not 50% loss not 36% (16%) 18% (3%) 52% (11%) achieved achievedachieved during 180 during 500 during 180 minutes (80) minutes minutes(60)  #1 100 (80) 425 (310) 85 (60) 29% (16%) 13% (3%) 47% (11%) #40  95(80) 390 (310) 70 (60)  6% (16%)  9% (3%) 24% (11%) #42 100 (80) 330(310) 75 (60) 24% (16%)  2% (3%) 37% (11%)

Analysis of the absorbance enables the time for which 50% loss of boundFe—S cluster is reached (i.e. a 50% absorbance decrease at 458 nm) foreach Test sample and each Control sample (in parenthesis table 3) to bedetermined. The data are then compared to determine whether the compoundof the invention stabilizes or destabilizes the NEET protein/Fe—Scluster binding.

Stabilisers of Fe—S cluster binding by the NEET proteins slow therelease of bound Fe—S (i.e. increase the time needed to reach 50% Fe—Scluster bound loss by more than 25% for the Test sample compared to theControl sample). As illustrated by table 3, at the concentrationstested, stabilisers of CISD1 Gene Product (mitoNEET) are the compounds#9, #18, #26, #2, #1, and #42. Stabilisers of CISD2 Gene Product (NAF-1)are the compounds #2, #1, and #40. Stabilisers of CISD3 Gene Product(Miner2) are the compounds #9, #18, #26, #2, #1, and #42.

As reported by table 3 (second part: “Residual cluster bound at end ofexperiment”), stabilizers may prevent the Fe—S cluster release by theNEET protein, the residual cluster bound at the end of the spectrometryexperiment being in a range of 36% to 73% meaning that 36% to 73% of theFe—S cluster remains bound to the total protein in the assay at the endof the experiment.

Example B4—Compounds Inhibit NFkB Activation in Response to TNFaStimulation

Compounds of the present invention have been tested for their capacityto inhibit NFκB. The results are shown in the following table.

TABLE 4 Compounds NFκB EC50 (μM) #18 1.1 #9 1.1 #111 2.2Materials and Methods

Construction of a NFκB Reporter Cell Line

The NFκB reporter construct was made by cloning 5 NFκB responsiveelements upstream of a NanoLuciferase reporter gene flanked by AAVS1genomic sequences.

NFκB Responsive element fused with NanoLuciferase and SV40 late Poly(A)signal was amplified from pNL3.2-NFκB-Nluc (Promega) using NFκB-NLUC-Fand NFκB-NLUC-R primers and inserted by Infusion (TaKaRa) in AAVS1SA-2A-puro-pA donor plasmid (Hockemeyer et al, Nat Biotechnol. 2009, 27,851-7) digested by Sall. pCRISPR AAVS1-T2 expressing a guide RNA (gRNA)to target human AAVS1 (T2 target sequence) was constructed by insertingAAVS1-T2A hybridized primers in pLentiCRISPR v2-blast (Sanjana et al,Nat Methods. 2014, 11, 783-4) digested by Bsmb1.

Oligonucleotide Sequences

(SEQ ID NO: 1) NFKB-NLUC-F: ggctctatggGTCGACGGCCTAACTGGCCGGTACC(SEQ ID NO: 2) NFKB-NLUC-R: agcttagtactGTCGACGATCAGCGGAAGAGCGCCCA(SEQ ID NO: 3) AAVS1-T2A-1 CACCGGGGGCCACTAGGGACAGGAT (SEQ ID NO: 4)AAVS1-T2A-2 AAACATCCTGTCCCTAGTGGCCCCC

A549 cells were transfected by the plasmids and puromycine selected for5 days (1 μg mL-1). Then clones were obtained by limiting dilution andselected to maximize TNFα dependent NFkB-NanoLuciferase induction.

NFκB Reporter Assay

The reporter cells were seeded on a 96-well plate for overnight withDMEM including 10% FBS. Test compounds were added at varyingconcentrations. The cells then were treated with 4 ng/ml TNFα(Peprotech, ref E251) in DMEM+10% FBS. NanoGlo luciferase assay(Promega) was carried out 6 hours later. Luminescence was measured usinga Spark 20M spectrofluorimeter (Tecan). Values were normalized to theluminescence measured in untreated cells.

The invention claimed is:
 1. A compound of formula (I):

wherein: R₁ represents: a 3-10 membered saturated ring selected from thegroup consisting a cycloalkyl, and a bridged carbocyclyl, wherein said3-10 membered ring is optionally substituted by at least one radicalselected from the group consisting of: a halogen, and a (C₁-C₆)alkyl, R₂represents: a hydrogen, a (C₁-C₆)alkyl, or a halogen, R₃ represents: aphenyl optionally substituted by at least one radical selected from thegroup consisting of: a morpholinyl, a —NH-tetrahydropyranyl, a—NH—(C₁-C₆)alkyl optionally substituted by a tetrahydropyranyl or  a(C₁-C₆)alkyloxy, an azetidinyl optionally substituted by a(C₁-C₆)alkyloxy a (C₁-C₆)alkyl optionally substituted by at least onehalogen, a halogen, and a (C₁-C₆)alkyloxy optionally substituted by atleast one halogen R₄ represents —COOH; and R₅ represents a hydrogen; ora stereoisomer or a pharmaceutical salt thereof.
 2. The compound ofclaim 1, wherein said compound is selected from the group consisting of:2-Benzamido-4-norbornan-2-yl-thiophene-3-carboxylic acid (Compound #9);2-Benzamido-4-cyclopentyl-thiophene-3-carboxylic acid (Compound #10);4-Cyclohexyl-2-[[4-(difluoromethoxy)benzoyl]amino]thiophene-3-carboxylicacid (Compound #11);2-Benzamido-5-chloro-4-cyclohexyl-thiophene-3-carboxylic acid (Compound#12);5-Chloro-4-cyclohexyl-2-[[4-(difluoromethoxy)benzoyl]amino]thiophene-3-carboxylicacid (Compound #13);5-Chloro-4-cyclohexyl-2-[(2-methylbenzoyl)amino]thiophene-3-carboxylicacid (Compound #14);5-Chloro-4-cyclohexyl-2-[(4-morpholinobenzoyl)amino]thiophene-3-carboxylicacid (Compound #15);2-Benzamido-5-chloro-4-cyclopentyl-thiophene-3-carboxylic acid (Compound#18); 4-Cyclohexyl-2-[(3,4-dimethoxybenzoyl)amino]thiophene-3-carboxylicacid (Compound #25); 2-Benzamido-4-cyclohexyl-thiophene-3-carboxylicacid (Compound #26);2-Benzamido-4-cyclohexyl-5-methyl-thiophene-3-carboxylic acid (Compound#27); 4-Cyclohexyl-2-[(4-morpholinobenzoyl)amino]thiophene-3-carboxylicacid (Compound #29);2-Benzamido-4-(3,3-difluorocyclobutyl)thiophene-3-carboxylic acid(Compound #35); 2-Benzamido-4-norcaran-7-yl-thiophene-3-carboxylic acid(Compound #37);2-Benzamido-4-(2,2,3,3-tetramethylcyclopropyl)thiophene-3-carboxylicacid (Compound #39);2-Benzamido-4-(trans-4-tert-butylcyclohexyl)thiophene-3-carboxylic acid(Compound #48);2-Benzamido-4-(cis-4-tert-butylcyclohexyl)thiophene-3-carboxylic acid(Compound #54);4-Cyclopentyl-2-[(4-morpholinobenzoyl)amino]thiophene-3-carboxylic acid(Compound #59); 4-Cyclopentyl-2-[[4-(tetrahydropyran-4-ylamino)benzoyl]amino]thiophene-3-carboxylic acid (Compound #60);4-Cyclopentyl-2-[[4-(2-methoxyethylamino)benzoyl]amino]thiophene-3-carboxylicacid (Compound #61);4-Cyclopentyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylicacid (Compound #62);2-Benzamido-4-(3-phenylcyclobutyl)thiophene-3-carboxylic acid (Compound#63); 4-Cyclopentyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylic acid (Compound #66);4-Cyclopentyl-2-[(3-morpholinobenzoyl)amino]thiophene-3-carboxylic acid(Compound #71); 2-Benzamido-4-cyclopropyl-thiophene-3-carboxylic acid(Compound #87);4-Cyclopropyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylicacid (Compound #88);4-Cyclopropyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylic acid (Compound #90);4-Cyclobutyl-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylicacid (Compound #97); 2-Benzamido-4-cyclobutyl-thiophene-3-carboxylicacid (Compound #98);4-Cyclobutyl-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylic acid (Compound #99);4-(3,3-Difluorocyclobutyl)-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino] thiophene-3-carboxylic acid (Compound #106);4-(3,3-Difluorocyclobutyl)-2-[[4-(3-methoxyazetidin-1-yl)benzoyl]amino]thiophene-3-carboxylicacid (Compound #107);2-[[4-(2-Methoxyethylamino)benzoyl]amino]-4-(1-methylcyclopropyl)thiophene-3-carboxylicacid (Compound #108);4-(1-Methylcyclopropyl)-2-[[4-(tetrahydropyran-4-ylmethylamino)benzoyl]amino]thiophene-3-carboxylicacid (Compound #111);2-[[4-(3-Methoxyazetidin-1-yl)benzoyl]amino]-4-(1-methylcyclopropyl)thiophene-3-carboxylic acid (Compound #112); and2-[[4-(3-Methoxyazetidin-1-yl)benzoyl]amino]-4-(1-methylcyclobutyl)thiophene-3-carboxylic acid (Compound #115).
 3. A method for treating adisease selected from the group consisting of an influenza virus Ainfection, influenza virus B infection, influenza virus C infection anda lung cancer comprising administering in a subject in need thereof acompound according to claim
 1. 4. A pharmaceutical compositioncomprising a compound according to claim 1 and an acceptablepharmaceutical excipient.
 5. The method according to claim 3, whereinthe subject that is being treated has an influenza virus A infection oran H1N1 influenza virus infection.
 6. The method according to claim 3,wherein the subject that is being treated has an influenza virus Binfection.
 7. The method according to claim 3, wherein the subject thatis being treated has an influenza virus C infection.
 8. The methodaccording to claim 3, wherein the subject that is being treated has lungcancer.